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201. In and out: adipose tissue lipid turnover in obesity and dyslipidemia

Author: Dominique Langin, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, medicine.medical_specialty, 030309 nutrition & dietetics, business.industry, Physiology, Adipose tissue, White adipose tissue, Cell Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Obesity, Article, 03 medical and health sciences, Endocrinology, Internal medicine, medicine, business, Molecular Biology, Dyslipidemia, 030304 developmental biology
Abstract: Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes. Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, lipid age was determined by measuring nuclear bomb test-derived 14C in adipocyte lipids. We report that during the average ten year life span of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate from fat tissue is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidemia, familial combined hyperlipidemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal play different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease.
Published: 2011
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202. Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B

Author: Antoine Ouvrard-Pascaud, Magali Vercauteren, Paul Mulder, Aurélie Waget, Elodie Gomez, Vincent Richard, Rémy Burcelin, Rob Hooft van Huijsduijnen, Baptiste Kurtz, Jean-Paul Henry, Christian Thuillez, Michel L. Tremblay, Marie Besnier, Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), MSPRI [Geneva, Switzerland], Goodman Cancer Research Center [Montréal] (GCRC), McGill University = Université McGill [Montréal, Canada], Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Brakenhielm, Ebba, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, Nouvelles Cibles Pharmacologiques de la Protection Endothéliale et de l'Insuffisance Cardiaque (EnVI), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), MS Project - Initiation (MSPRI), Apollo SSC Genève, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Cardiac output, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Cardiac fibrosis, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine.medical_treatment, Myocardial Infarction, Gene Expression, 030204 cardiovascular system & hematology, Mice, 0302 clinical medicine, MESH: Animals, Enzyme Inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 1, 0303 health sciences, Mice, Inbred BALB C, Ventricular Remodeling, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Myocardial Infarction, MESH: Insulin Resistance, medicine.anatomical_structure, MESH: Enzyme Inhibitors, Echocardiography, Cardiology, cardiovascular system, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Nitric Oxide Synthase, Cardiology and Cardiovascular Medicine, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, MESH: Hemodynamics, MESH: Myocardium, MESH: Gene Expression, Endothelium, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Inbred BALB C, MESH: Ventricular Remodeling, 03 medical and health sciences, Insulin resistance, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Mice, Inbred C57BL, Internal medicine, Diabetes mellitus, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Ventricular remodeling, Molecular Biology, MESH: Mice, 030304 developmental biology, Heart Failure, business.industry, Insulin, Myocardium, Hemodynamics, medicine.disease, MESH: Male, MESH: Protein Tyrosine Phosphatase, Non-Receptor Type 1, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, MESH: Gene Deletion, Heart failure, MESH: Heart Failure, MESH: Echocardiography, MESH: Disease Models, Animal, Insulin Resistance, Nitric Oxide Synthase, business, Gene Deletion
Abstract: International audience; Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF). We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure.
Published: 2011
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203. Role of endothelial AADC in cardiac synthesis of serotonin and nitrates accumulation

Author: Naïma Hanoun, Jean-Simon Rech, Céline Frugier, Pierre Sicard, Charlotte Rouzaud-Laborde, Denis Calise, Marie-Hélène Seguelas, Angelo Parini, Céline Mias, Nathalie Pizzinat, Ipek Baysal, Pôle Pharmacie, CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pôle pharmacie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise
Subjects: Anatomy and Physiology, Mouse, Enzyme Metabolism, lcsh:Medicine, Nitrogen Metabolism, 030204 cardiovascular system & hematology, Tryptophan Hydroxylase, Cardiovascular, Cardiovascular System, Biochemistry, 5-Hydroxytryptophan, Rats, Sprague-Dawley, chemistry.chemical_compound, Mice, 0302 clinical medicine, Molecular Cell Biology, Aromatic Amino Acid Decarboxylase Inhibitors, Myocytes, Cardiac, lcsh:Science, Chromatography, High Pressure Liquid, 0303 health sciences, Multidisciplinary, TPH1, Reverse Transcriptase Polymerase Chain Reaction, Degranulation, Heart, Animal Models, 3. Good health, Enzymes, Nitric oxide synthase, Aromatic-L-Amino-Acid Decarboxylases, Nitric Oxide Pathway, Medicine, Cellular Types, Research Article, medicine.medical_specialty, Serotonin, Cell Physiology, Blotting, Western, Aortic Diseases, Biology, Biosynthesis, Cardiovascular Pharmacology, Nitric oxide, 03 medical and health sciences, Model Organisms, Internal medicine, medicine, Animals, Platelet activation, 030304 developmental biology, Nitrates, Myocardium, lcsh:R, Endothelial Cells, Tryptophan hydroxylase, Rats, Endocrinology, Metabolism, chemistry, biology.protein, Rat, lcsh:Q
Abstract: International audience; Serotonin (5-HT) regulates different cardiac functions by acting directly on cardiomyocytes, fibroblasts and endothelial cells. Today, it is widely accepted that activated platelets represent a major source of 5-HT. In contrast, a supposed production of 5-HT in the heart is still controversial. To address this issue, we investigated the expression and localization of 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and L-aromatic amino acid decarboxylase (AADC) in the heart. We also evaluated their involvement in cardiac production of 5-HT. TPH1 was weakly expressed in mouse and rat heart and appeared restricted to mast cells. Degranulation of mast cells by compound 48/80 did not modify 5-HT cardiac content in mice. Western blots and immunolabelling experiments showed an abundant expression of AADC in the mouse and rat heart and its co-localization with endothelial cells. Incubation of cardiac homogenate with the AADC substrate (5-hydroxy-L-tryptophan) 5-HTP or intraperitoneal injection of 5-HTP in mice significantly increased cardiac 5-HT. These effects were prevented by the AADC inhibitor benserazide. Finally, 5-HTP administration in mice increased phosphorylation of aortic nitric oxide synthase 3 at Ser (1177) as well as accumulation of nitrates in cardiac tissue. This suggests that the increase in 5-HT production by AADC leads to activation of endothelial and cardiac nitric oxide pathway. These data show that endothelial AADC plays an important role in cardiac synthesis of 5-HT and possibly in 5-HT-dependent regulation of nitric oxide generation.
Published: 2011
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204. Activation function 2 (AF2) of estrogen receptor-{alpha} is required for the atheroprotective action of estradiol but not to accelerate endothelial healing

Author: Andrée Krust, Pierre Chambon, Gilles Flouriot, Pierre Gourdy, Jean-François Arnal, Alain-Pierre Gadeau, Audrey Billon-Galés, Hortense Berges, Coralie Fontaine, Françoise Lenfant, Céline E. Toutain, Anne Abot, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Adaptation cardiovasculaire à l'ischemie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), and Simon, Marie Francoise
Subjects: Transcriptional Activation, medicine.medical_specialty, Endothelium, medicine.drug_class, [SDV]Life Sciences [q-bio], Estrogen receptor, 030204 cardiovascular system & hematology, Biology, Protective Agents, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Internal medicine, medicine, Animals, Humans, Aorta, 030304 developmental biology, Mice, Knockout, Regulation of gene expression, Wound Healing, 0303 health sciences, Multidisciplinary, Estradiol, Kinase, Body Weight, Uterus, Estrogen Receptor alpha, Reproducibility of Results, Hep G2 Cells, Organ Size, Biological Sciences, Atherosclerosis, Cell biology, [SDV] Life Sciences [q-bio], Endocrinology, medicine.anatomical_structure, Gene Expression Regulation, Cell culture, Estrogen, Female, Endothelium, Vascular, Estrogen receptor alpha, HeLa Cells
Abstract: 17β-Estradiol (E2) regulates estrogen receptor-α (ERα) target gene transcription through the two independent activation functions (AFs), AF1 and AF2, located in the N-terminal and ligand binding domain of ERα, respectively. We previously reported that ERα is required for the E2 atheroprotective action as well as for its accelerative action on endothelial healing, but its AF1 function is dispensable. Here, we investigated the role of ERαAF2 in these two major beneficial actions of E2 by electively targeting ERαAF2 (named ERαAF2 0 ) . Our results prove four points. ( i ) Compared with WT ERα, the ability of ERαAF2 0 to stimulate the C3 complement or the estrogen response element-thymidine kinase promoter in two cell lines was dramatically decreased, confirming the importance of AF2 in the E2-induced transcriptional activity of ERα. ( ii ) The uterotrophic action of E2 was totally absent in ERαAF2 0 mice, showing the crucial role of ERαAF2 in E2-induced uterus hyperplasia. ( iii ) ERαAF2 was dispensable for the accelerative action of E2 on endothelial healing, underlining the functionality of ERαAF2 0 in vivo. ( iv ) Finally, the atheroprotective effect of E2 was abrogated in ERαAF2 0 LDL-r −/− mice. Thus, whereas ERαAF1 and ERαAF2 are both required for the uterotrophic action of E2, we show that only ERαAF2 is necessary for its atheroprotective effect.
Published: 2011
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205. Apelin, diabetes, and obesity

Author: Camille Attané, Philippe Valet, Claude Knauf, Isabelle Castan-Laurell, Cédric Dray, Thibaut Duparc, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Adipokine, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Adipokines, Diabetes mellitus, Internal medicine, medicine, Animals, Humans, Obesity, Receptor, 030304 developmental biology, 0303 health sciences, Lipid metabolism, Lipid Metabolism, medicine.disease, 3. Good health, Apelin, Disease Models, Animal, Glucose, Diabetes Mellitus, Type 2, Intercellular Signaling Peptides and Proteins, Signal transduction, Energy Metabolism
Abstract: International audience; Apelin is a peptide known as the ligand of the G-protein-coupled receptor APJ. Several active apelin forms exist such as apelin-36, apelin-17, apelin-13, and the pyroglutamated form of apelin-13. Apelin and APJ are expressed in the central nervous system, particularly in the hypothalamus and in many peripheral tissues. Apelin has been shown to be involved in the regulation of cardiovascular and fluid homeostasis, food intake, cell proliferation, and angiogenesis. In addition to be an ubiquitous peptide, apelin is also produced and secreted by adipocytes and thus considered as an adipokine. This has opened a new field of investigation establishing a link between apelin and metabolic disorders (obesity, type 2 diabetes, etc.) which is the focus of the present review. Several studies, but not all, have reported an increase of plasma apelin concentrations in humans and in animal models with different metabolic pathologies. Moreover, important roles for apelin both in glucose and lipid metabolism have been highlighted as well as the associated signaling pathways. Apelin appears as a beneficial adipokine with anti-obesity and anti-diabetic properties and thus as a promising therapeutic target in metabolic disorders.
Published: 2011
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206. PKC-delta and PKC-epsilon: Foes of the same family or strangers?

Author: Nicolas Duquesnes, Frank Lezoualc'h, Bertrand Crozatier, Cardiopathies et mort subite [ERL 3147], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes (UN), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Signalisation et physiopathologie cardiaque, Université Paris-Sud - Paris 11 (UP11)-IFR141-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, and Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Protein Kinase C-alpha, Guinea Pigs, Myocardial Ischemia, Apoptosis, Protein Kinase C-epsilon, 030204 cardiovascular system & hematology, Biology, Serine, 03 medical and health sciences, Mice, 0302 clinical medicine, Animals, Humans, Threonine, Enzyme Inhibitors, Molecular Biology, Protein kinase C, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Kinase, Cell growth, Myocardium, Cell Differentiation, Cell biology, Protein Structure, Tertiary, Rats, Enzyme Activation, Isoenzymes, Protein Kinase C-delta, Enzyme, chemistry, Biochemistry, Organ Specificity, Tetradecanoylphorbol Acetate, Hypertrophy, Left Ventricular, Rabbits, Signal transduction, Cardiology and Cardiovascular Medicine, Protein Binding, Signal Transduction
Abstract: International audience; Protein kinase C (PKC) is a family of 10 serine/threonine kinases divided into 3 subfamilies, classical, novel and atypical classes. Two PKC isozymes of the novel group, PKCε and PKCδ, have different and sometimes opposite effects. PKCε stimulates cell growth and differentiation while PKCδ is apoptotic. In the heart, they are among the most expressed PKC isozymes and they are opposed in the preconditioning process with a positive role of PKCε and an inhibiting role of PKCδ. The goal of this review is to analyze the structural differences of these 2 enzymes that may explain their different behaviors and properties.
Published: 2011
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207. Cancer-associated adipocytes promotes breast tumor radioresistance

Author: Ludivine Bochet, Catherine Muller, Sandrine Imbert, Bernard Salles, Aline Meulle, Philippe Valet, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Bochet, Ludivine, Meulle, Aline, Imbert, Sandrine, Salles, Bernard, Valet, Philippe, and Muller, Catherine
Subjects: Ionizing radiation, medicine.medical_specialty, Programmed cell death, Cell Survival, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biophysics, Breast Neoplasms, Interleukin 6, Radiation Tolerance, Biochemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Adipocytes, Ionizing radiation, Breast cance,r Radioresistance, Interleukin 6, Radioresistance, Internal medicine, medicine, Adipocytes, Animals, Humans, Radiosensitivity, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, Interleukin-6, Kinase, Lymphokine, Cell Biology, Coculture Techniques, [SDV] Life Sciences [q-bio], Cytokine, Endocrinology, Apoptosis, 030220 oncology & carcinogenesis, Checkpoint Kinase 1, Cancer research, biology.protein, Female, Protein Kinases
Abstract: International audience; Mature adipocytes are excellent candidates to influence tumor behavior through heterotypic signaling processes since these cells produce hormones, growth factors, cytokines and other molecules, a heterogeneous group of molecules named adipokines. Using a 2D coculture system, we demonstrate that breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance and an earlier and higher increase in the effector kinase Chk1, a phenotype that was associated with decreased cell death as compared to tumor cells grown alone. Interestingly, the adipocytes-induced tumor changes taking place during the coculture time preceding the exposure to IR were sufficient to confer the radioresistant effect. Notorious among the changes brought by adipocytes was the significant increase of IL-6 expression in tumor cells, whose activity may well account for the observed tumor cell protection from IR toxicity. Indeed, our data confirmed the protective role of this cytokine as tumor cells incubated after irradiation with recombinant IL-6 exhibit an increased in Chk1 phosphorylation and a radioresistant phenotype, thus far recapitulating the effects observed in the presence of adipocytes. Our current study sheds light on a new role of tumor-surrounding adipocytes in fostering a radioresistant phenotype in breast tumors, a finding that might have important clinical implications in obese patients that frequently exhibit aggressive diseases.
Published: 2011
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208. Estradiol administration controls eosinophilia through estrogen receptor-alpha activation during acute peritoneal inflammation

Author: Jean-Charles Guéry, Pierre Gourdy, Victorine Douin-Echinard, Jean-François Arnal, Françoise Lenfant, Audrey Billon-Galés, Florence Trémollières, Bertrand Calippe, Francis Bayard, Coralie Fontaine, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, medicine.drug_class, Immunology, Inflammation, Apoptosis, Cell Separation, Peritonitis, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Internal medicine, Eosinophilia, medicine, Immunology and Allergy, Animals, Interleukin 5, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Estradiol, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Estrogen Receptor alpha, Estrogens, Cell Biology, Eosinophil, respiratory system, Flow Cytometry, Eosinophils, Mice, Inbred C57BL, Chemotaxis, Leukocyte, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, Estrogen, Female, medicine.symptom, Interleukin-5, business, Estrogen receptor alpha, 030215 immunology
Abstract: Estrogens influence the incidence and the course of numerous immune or inflammatory diseases in humans and in experimental models. For instance, estrogens prevent the accumulation of granulocytes in acute inflammatory murine models, but the respective actions on neutrophil and eosinophil trafficking remain to be clarified. We demonstrate here that in a model of TGC-induced sterile peritonitis in ovx mice, chronic E2 administration electively and strongly inhibited peritoneal eosinophil accumulation. E2 decreased BM eosinophil number, contributing to a marked prevention of the TGC-induced eosinophil blood mobilization. These effects on eosinophil mobilization and peritoneal accumulation were abolished in ER-α−/− mice, demonstrating the crucial role of this nuclear receptor. Grafting ER-α−/− mice with ER-α+/+ BM cells restored the suppressive effect of E2 on peritoneal eosinophilia, although the action on eosinophil blood mobilization was still abrogated. We therefore explored additional mechanisms and found that E2 reduced the peritoneal concentrations of key eosinophil prosurvival factors (IL-5, IL-9, and IL-25) and enhanced eosinophil apoptosis during the inflammatory process. Furthermore, this proapoptotic effect of E2 was abrogated in IL-5-overexpressing Tg mice. To conclude, we demonstrate for the first time that ER-α activation by exogenous E2 administration strongly inhibits eosinophil accumulation during acute inflammation in a nonreproductive target site for estrogen through combined actions on eosinophil mobilization and apoptosis. This specific, suppressive effect of chronic E2 replacement therapy on eosinophils has to be integrated to further understand the evolution of eosinophil-associated diseases in menopausal women.
Published: 2011
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209. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept

Author: Pascale Klopp, Jason S. Iacovoni, Joël Doré, Céline Lange, Olivier Bouchez, Rémy Burcelin, Jérôme Mariette, Jacques Amar, Olivier Lantieri, Marie-Aline Charles, Matteo Serino, L. Perez, Christophe Klopp, Michael Courtney, B. Balkau, Michel Marre, Chantal Chabo, Patricia Lepage, Stanislas Mondot, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Médecine Interne et Hypertension Artérielle [Toulouse], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de Biométrie et Intelligence Artificielle de Toulouse [Castanet-Tolosan] (UBIA), Institut National de la Recherche Agronomique (INRA)-Plateforme bioinformatique du GIS GENOTOUL - Génopole Toulouse Midi-Pyrénées, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaiomer, Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut inter-Régional pour la SAnté (IRSA), This work was funded by the Agence Nationale de la Recherche (French national research agency) (to R. Burcelin) and by the Societe Francophone de Diabete (to B. Balkau). The D.E.S.I.R. study has been supported by Inserm contracts with CNAMTS, Lilly, Novartis Pharma and sanofi-aventis, by Inserm (Reseaux en Sante Publique, Interactions entre les determinants de la sante, Cohortes Sante TGIR 2008), the Association Diabete Risque Vasculaire, the Federation Francaise de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Societe Francophone du Diabete, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics., Service d'hypertension artérielle et thérapeutique [CHU Toulouse] (HTA et thérapeutique), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biométrie et Intelligence Artificielle (ancêtre de MIAT) (UBIA), Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), VAIOMER SAS, VAIOMMER, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), and Plateforme bioinformatique du GIS GENOTOUL - Génopole Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: Male, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], [MATH] Mathematics [math], 0302 clinical medicine, MESH: Metabolic Syndrome X, RNA, Ribosomal, 16S, MESH: Obesity, Longitudinal Studies, [MATH]Mathematics [math], MESH: Longitudinal Studies, Genetics, MESH: Aged, Metabolic Syndrome, 0303 health sciences, education.field_of_study, MESH: Middle Aged, biology, Middle Aged, MESH: Case-Control Studies, 3. Good health, [SDV] Life Sciences [q-bio], MESH: RNA, Ribosomal, 16S, Obesity, Abdominal, Female, France, MESH: Diabetes Mellitus, Type 2, Adult, Population, abdominal adiposity, 030209 endocrinology & metabolism, [INFO] Computer Science [cs], MESH: Obesity, Abdominal, 03 medical and health sciences, endocrinology, Diabetes mellitus, Internal Medicine, medicine, microbiota, Humans, [INFO]Computer Science [cs], Obesity, education, 16s rdna gene, 030304 developmental biology, Aged, MESH: Humans, Bacteria, Case-control study, MESH: Biological Markers, MESH: Adult, Human physiology, MESH: Metagenome, biology.organism_classification, medicine.disease, MESH: Male, MESH: France, MESH: Bacteria, Diabetes Mellitus, Type 2, Case-Control Studies, Immunology, Metagenome, metabolism, MESH: Female, Biomarkers
Abstract: Chantier qualité GA; International audience; AIMS/HYPOTHESIS: Evidence suggests that bacterial components in blood could play an early role in events leading to diabetes. To test this hypothesis, we studied the capacity of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes and obesity in a general population. METHODS: Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) is a longitudinal study with the primary aim of describing the history of the metabolic syndrome. The 16S rDNA concentration was measured in blood at baseline and its relationship with incident diabetes and obesity over 9 years of follow-up was assessed. In addition, in a nested case-control study in which participants later developed diabetes, bacterial phylotypes present in blood were identified by pyrosequencing of the overall 16S rDNA gene content. RESULTS: We analysed 3,280 participants without diabetes or obesity at baseline. The 16S rDNA concentration was higher in those destined to have diabetes. No difference was observed regarding obesity. However, the 16S rDNA concentration was higher in those who had abdominal adiposity at the end of follow-up. The adjusted OR (95% CIs) for incident diabetes and for abdominal adiposity were 1.35 (1.11, 1.60), p = 0.002 and 1.18 (1.03, 1.34), p = 0.01, respectively. Moreover, pyrosequencing analyses showed that participants destined to have diabetes and the controls shared a core blood microbiota, mostly composed of the Proteobacteria phylum (85-90%). CONCLUSIONS/INTERPRETATION: 16S rDNA was shown to be an independent marker of the risk of diabetes. These findings are evidence for the concept that tissue bacteria are involved in the onset of diabetes in humans.
Published: 2011
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210. Lipid-Induced Peroxidation in the Intestine Is Involved in Glucose Homeostasis Imbalance in Mice

Author: Aurélie Waget, Matteo Serino, Jean-Claude Thiers, Gaelle Payros, Rémy Burcelin, Amélie Lacombe, Serge Luquet, Jessica Denom, Myriam Masseboeuf, Catherine Kabani, Céline Cruciani-Guglielmacci, Nicolas Marsollier, Anne Nègre-Salvayre, Christophe Magnan, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), RB is the recipient of a grant from the European Association for the Study of Diabetes (EASD) and Amylin. CM is the recipient of funding from the 'Agence Nationale de la Recherche' (France): ANR-07-PHYSIO, Simon, Marie Francoise, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Central Nervous System, Anatomy and Physiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Guanidines, Jejunum, Lipid peroxidation, chemistry.chemical_compound, Mice, 0302 clinical medicine, Endocrinology, Integrative Physiology, Glucose homeostasis, Homeostasis, Insulin, Intestinal Mucosa, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Intestines, medicine.anatomical_structure, Medicine, Research Article, medicine.medical_specialty, Science, Endocrine System, Biology, Neurological System, 03 medical and health sciences, Insulin resistance, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, 030304 developmental biology, Nutrition, Diabetic Endocrinology, Endocrine Physiology, medicine.disease, Vagus nerve, Oxidative Stress, Glucose, chemistry, Metabolic Disorders, Duodenum, Lipid Peroxidation, Insulin Resistance, Physiological Processes, Digestive System, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BACKGROUND: Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. METHODOLOGY/PRINCIPAL FINDINGS: An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. CONCLUSIONS/SIGNIFICANCE: Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity.
Published: 2011
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211. From in vivo gene targeting of Estrogen Receptors to Optimisation of their Modulation in Menopause

Author: Arnal, Jean-François, Lenfant, Françoise, Flouriot, Gilles, Tremollières, Florence, Laurell, Henrik, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Gourdy, Pierre, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Récepteur des oestrogènes et destinée cellulaire, Interactions cellulaires et moléculaires (ICM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: uterus, [SDV]Life Sciences [q-bio], Estrogen Antagonists, Reviews, artery, menopause, oestradiol, SERM, [SDV] Life Sciences [q-bio], Receptors, Estrogen, Gene Targeting, Humans, atheroma, Female, skin and connective tissue diseases
Abstract: International audience; The ancestral status of estrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of estrogens, and in particular of 17β-estradiol (E2). Indeed, in addition to their well described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes prevention of osteoporosis, atheroma and type 2 diabetes,... but also promotion of uterus and breast cancer growth. Thus, the major challenge consists in uncoupling some beneficial actions from other deleterious ones, i.e. selective ER modulation. Tamoxifen and raloxifen are already used as they prevent the recurrence of breast cancer, and mimic estrogen action mainly on bone. Both E2 and tamoxifen exhibit a proliferative and thus protumoral action on the endometrium. Activation of ER alpha (ERα) and beta (ERβ) regulates target gene transcription (genomic action) through two independent activation functions AF-1 and AF-2, but can also elicit rapid membrane initiated steroid signals. In the present review, we attempted to summarize recent advances provided by the in vivo molecular "dissection" of ERα, allowing the uncoupling of some of its actions, and potentially paving the way to optimized selective ER modulators.
Published: 2011
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212. Expression of nitric oxide synthases in primary ciliary dyskinesia

Author: Elie Serrano, Séverine Valmary, Jean-François Arnal, Bruno Degano, Pierre Brousset, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie cardiovasculaire et prévention, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Département de physiologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service ORL, otoneurologie et ORL pédiatrique [CHU Toulouse], Pôle Céphalique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oto-rhino-laryngologie, and CHU Toulouse [Toulouse]
Subjects: Adult, Pathology, medicine.medical_specialty, Adolescent, Nitric Oxide Synthase Type III, Nitric Oxide Synthase Type II, Nose, Nitric Oxide, Gene Expression Regulation, Enzymologic, Pathology and Forensic Medicine, Nitric oxide, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Nasal Polyps, Internal medicine, Ethidium, medicine, otorhinolaryngologic diseases, Humans, Nasal polyps, In patient, Child, 030304 developmental biology, Primary ciliary dyskinesia, Demography, Fluorescent Dyes, 0303 health sciences, biology, Chemistry, Kartagener Syndrome, NADPH Dehydrogenase, Nitric oxide synthase 2, Middle Aged, respiratory system, medicine.disease, Nitric oxide synthase, Endocrinology, 030228 respiratory system, Case-Control Studies, biology.protein, Airway, Reactive Oxygen Species, Immunostaining
Abstract: International audience; Nitric oxide is believed to play a central role in nonspecific defense of upper airways. Patients with primary ciliary dyskinesia have very low concentration of nasal nitric oxide, which may contribute to the chronic upper airway diseases encountered by these patients. The mechanisms underlying this drop of nasal nitric oxide in primary ciliary dyskinesia are still unknown. The goal of the present work was to study nitric oxide synthases expression in upper airway tissues from patients with primary ciliary dyskinesia. For this purpose, 5 patients with primary ciliary dyskinesia and 10 nonallergic age-matched patients without primary ciliary dyskinesia undergoing nasal polypectomy were included. Nasal nitric oxide concentration was measured before polypectomy, and nitric oxide synthase expression and function were studied in nasal polyps. The nasal nitric oxide in patients with primary ciliary dyskinesia was lower than that in patients without primary ciliary dyskinesia (13 [9-16] ppb versus 210 [167-254] ppb, P < .0001). Nitric oxide synthase 2 immunostaining was prominent at the apical part of the ciliated epithelial cells and was similar in both groups. Nitric oxide synthase 3 staining was restricted to endothelial cells in both groups. In addition, reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase activity was superimposable to nitric oxide synthases 2 and 3 immunostaining, suggesting a preserved NADPH-activity of nitric oxide synthase. We therefore conclude that the drop in nasal nitric oxide in patients with primary ciliary dyskinesia is not secondary to the loss of nitric oxide synthase expression.
Published: 2011
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213. Genetic association and gene expression analysis identify FGFR1 as a new susceptibility gene for human obesity

Author: Anne Bouloumié, Karine Clément, Hong Jiao, Dominique Langin, Mikael Rydén, Anders Hamsten, Pilar Galan, Magdalena Taube, Ingrid Dahlman, Anna Benrick, Cyrille Debard, Chantal Simon, Martine Laville, John-Olov Jansson, Angela Silveira, Caroline Hansson, Corneliu Henegar, Tomas Axelsson, Peter Arner, Juha Kere, Hubert Vidal, Karin Dahlman-Wright, Anke Hinney, Niklas Mejhert, Suzanne L. Dickson, Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Clinical Research Centre, Karolinska University Hospital [Stockholm], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-University of Gothenburg ( GU ), Régulations métaboliques, nutrition et diabètes - UM55 ( RMND UM55 ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Atherosclerosis Research Unit, Karolinska Institutet [Stockholm]-Department of Medicine Solna-Cardiovascular Genetics Group, Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'épidémiologie et de santé publique, Université Louis Pasteur - Strasbourg I, Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of medical sciences, Uppsala University-Molecular Medicine-Science for Life Laboratory, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-University of Gothenburg (GU), Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Sahlgrenska Academy at University of Gothenburg [Göteborg], Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Science for Life Laboratory [Solna], Royal Institute of Technology [Stockholm] (KTH ), AFA Insurance, Swedish Heart and Lung Foundation, Swedish Research Council [8691], Novo Nordic Foundation, Swedish Diabetes Association, Knut and Alice Wallenberg Foundation, Stockholm County Council [562183], European Commission [LSHM-CT-2005-018734, ADAPT FP7-Health-2007-A], Direction de la Recherche Clinique/Assistance Publique-Hopitaux de Paris, Programmes Hospitaliers de Recherche Clinique [AOR 02076], Le site de l'Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques, region Ile de France, Swedish Medical Research Council [VR k2007-54x-20328-013], European Union [FP7-HEALTH-2009-241592, FP7-KBBE-2009-3-245009], ALF Goteborg [SU7601], Swedish Foundation for Strategic Research [A305-188], German Ministry of Education and Research (NGFNplus) [01GS0820], Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
Subjects: Male, Fibroblast Growth Factor, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Messenger, Medizin, Adipose tissue, Appetite, Biochemistry, Rats, Sprague-Dawley, 0302 clinical medicine, Endocrinology, Odds Ratio, Child, media_common, 2. Zero hunger, 0303 health sciences, education.field_of_study, Blotting, Reverse Transcriptase Polymerase Chain Reaction, Skeletal, Single Nucleotide, Adipose Tissue, Muscle, Female, Western, Type 1, Receptor, Adult, medicine.medical_specialty, Adolescent, Animals, Chi-Square Distribution, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Hypothalamus, Obesity, Polymorphism, RNA, Rats, Sprague-Dawley, media_common.quotation_subject, Population, Blotting, Western, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Context (language use), Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Receptor, Fibroblast Growth Factor, Type 1, education, Muscle, Skeletal, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, business.industry, Biochemistry (medical), Odds ratio, Fat cell differentiation, medicine.disease, stomatognathic diseases, business
Abstract: International audience; CONTEXT: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. OBJECTIVE: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. DESIGN: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. SETTING: General community and referral centers for specialized care was the setting for the study. PARTICIPANTS: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. MAIN OUTCOME MEASURES: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. RESULTS: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 × 10(-6), which was P = 7.0 × 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). CONCLUSIONS: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.
Published: 2011
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214. Essential thrombocythemia and pregnancy

Author: Jean-François Arnal, Christophe Vayssière, Olivier Parant, Marie-Cécile Valéra, Bernard Payrastre, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Chirurgie Dentaire, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de gynécologie obstétrique, CHU Toulouse [Toulouse]-Hôpital Paule de Viguier, CHU Toulouse [Toulouse], Laboratoire d'Hématologie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Université Fédérale Toulouse Midi-Pyrénées, Service Gynécologie [CHU Toulouse], Pôle Femme-Mère-Couple [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise
Subjects: medicine.medical_specialty, 030204 cardiovascular system & hematology, Abortion, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Risk Factors, medicine, Humans, Myeloproliferative neoplasm, Fetus, Placental abruption, Thrombocytosis, Obstetrics, Essential thrombocythemia, business.industry, Pregnancy Complications, Hematologic, Pregnancy Outcome, Obstetrics and Gynecology, medicine.disease, 3. Good health, Reproductive Medicine, 030220 oncology & carcinogenesis, Female, Complication, business, Thrombocythemia, Essential
Abstract: International audience; Essential thrombocythaemia (ET) is an acquired myeloproliferative neoplasm, characterised by persistent thrombocytosis and a tendency for either thrombosis or haemorrhage. Among myeloproliferative neoplasms, ET is the most prevalent in young women, which constitute a special group due to their childbearing potential. An increased risk of fetal and maternal complications has been demonstrated in patients with ET. The most common pregnancy-related complication is spontaneous abortion during the first trimester. Recurrent abortion, fetal growth restriction, stillbirth and placental abruption are less frequent. Maternal complications are relatively rare and essentially represented by thromboembolic and bleeding events. Here we summarize the literature describing pregnancy and its outcome in patients with ET and discuss some recommendations for the management of pregnancy.
Published: 2011
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215. Antiatherogenic Effect of Bisvanillyl-Hydralazone, a New Hydralazine Derivative with Antioxidant, Carbonyl Scavenger, and Antiapoptotic Properties

Author: Marie-Hélène Grazide, Nadji Belkheiri, Koji Uchida, Benaissa Bouguerne, Cécile Vindis, Robert Salvayre, Florence Bedos-Belval, Hubert Duran, Michel Baltas, Anne Nègre-Salvayre, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences-Nagoya University, Université Fédérale Toulouse Midi-Pyrénées, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP)
Subjects: Male, Antioxidant, Physiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Apoptosis, 030204 cardiovascular system & hematology, medicine.disease_cause, Biochemistry, Antioxidants, Lipid peroxidation, Protein Carbonylation, chemistry.chemical_compound, Mice, 0302 clinical medicine, [CHIM] Chemical Sciences, Hydrogen peroxide, Cells, Cultured, Chemokine CCL2, ComputingMilieux_MISCELLANEOUS, General Environmental Science, Chelating Agents, chemistry.chemical_classification, Mice, Knockout, 0303 health sciences, Superoxide, Hydralazine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Plaque, Atherosclerotic, 3. Good health, Lipoproteins, LDL, lipids (amino acids, peptides, and proteins), medicine.drug, Bisvanillyl-Hydralazone, Proteasome Endopeptidase Complex, 03 medical and health sciences, medicine, Cell Adhesion, [CHIM]Chemical Sciences, Animals, Humans, Molecular Biology, 030304 developmental biology, Reactive oxygen species, Antiapoptotic Properties, Guaiacol, Endothelial Cells, Cell Biology, Atherosclerosis, Enzyme Activation, Oxidative Stress, chemistry, Hydralazine Derivative, General Earth and Planetary Sciences, Lipid Peroxidation, Reactive Oxygen Species, Carbonyl Scavenger, Oxidative stress, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Lipoprotein, Foam Cells
Abstract: International audience; Reactive oxygen species (ROS) generated within the vascular wall trigger low-density lipoprotein (LDL) oxidation, lipid peroxidation, and carbonyl stress that are involved in atherogenesis. We recently reported that the antihypertensive drug, hydralazine, exhibits carbonyl scavenger and antiatherogenic properties, but only moderate antioxidant activity, so that high concentrations are required for inhibiting LDL oxidation. We aimed to develop agents sharing both antioxidant and carbonyl scavenger properties. We have synthesized a new hydralazine derivative, the bisvanillyl-hydralazone (BVH). BVH strongly inhibited LDL oxidation induced by copper and by human endothelial cells (HMEC-1), and prevented the formation of macrophagic foam cells. BVH reduced both the extracellular generation of ROS (superoxide anion and hydrogen peroxide) induced by oxidized LDL (oxLDL), as well as intracellular oxidative stress and proteasome activation, NFkappaB activation, and oxLDL-mediated proinflammatory signaling. In parallel, BVH prevented the carbonyl stress induced by oxLDL on cellular proteins, and blocked the apoptotic cascade as assessed by the inhibition of Bid cleavage, cytochrome C release, and DEVDase activation. Lastly, BVH prevented atherogenesis and carbonyl stress in apoE(-/-) mice. In conclusion, BVH is the prototype of a new class of antioxidant and carbonyl scavenger agents designed for new therapeutical approaches in atherosclerosis.
Published: 2011
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216. Adipose-specific disruption of autotaxin enhances nutritional fattening and reduces plasma lysophosphatidic acid

Author: Philippe Valet, Sandra Grès, Jean Sébastien Saulnier-Blache, Wouter H. Moolenaar, Charlotte Guigné, Estelle Wanecq, Chloé Rancoule, R. Dusaulcy, Laurens A. van Meeteren, André Colom, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of cell biology, The Netherlands Cancer Institute-Center for Biomedical Genetics, This work was supported by grants from the INSERM, the Fondation pour la Recherche Médicale (grant # DRM20101220459), and the Dutch Cancer Society. R. Dusaulcy and C. Rancoule were supported by a grant from the Ministère de l'Education Nationale de la Recherche et de la Technologie (France)., and Simon, Marie Francoise
Subjects: Blood Glucose, Male, Adipose tissue, White adipose tissue, Biochemistry, Mice, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Adipose Tissue, Brown, Adipocyte, Brown adipose tissue, Lysophosphatidic acid, Adipocytes, Insulin, Pyrophosphatases, Research Articles, Adiposity, Mice, Knockout, 2. Zero hunger, 0303 health sciences, Leptin, Founder Effect, high-fat diet, medicine.anatomical_structure, Phosphodiesterase I, 030220 oncology & carcinogenesis, Female, lipids (amino acids, peptides, and proteins), Autotaxin, medicine.medical_specialty, Adipose Tissue, White, QD415-436, Biology, adipocyte, 03 medical and health sciences, Multienzyme Complexes, Internal medicine, medicine, Animals, Obesity, Cell Size, 030304 developmental biology, Adiponectin, Phosphoric Diester Hydrolases, Cell Biology, Glucose Tolerance Test, Dietary Fats, PPAR gamma, Disease Models, Animal, chemistry, Lysophospholipids, Gene Deletion
Abstract: International audience; Autotaxin (ATX) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA). ATX is secreted by adipose tissue and its expression is enhanced in obese/insulin-resistant individuals. Here, we analyzed the specific contribution of adipose-ATX to fat expansion associated with nutritional obesity and its consequences on plasma LPA levels. We established ATX(F/F)/aP2-Cre (FATX-KO) transgenic mice carrying a null ATX allele specifically in adipose tissue. FATX-KO mice and their control littermates were fed either a normal or a high-fat diet (HFD) (45% fat) for 13 weeks. FATX-KO mice showed a strong decrease (up to 90%) in ATX expression in white and brown adipose tissue, but not in other ATX-expressing organs. This was associated with a 38% reduction in plasma LPA levels. When fed an HFD, FATX-KO mice showed a higher fat mass and a higher adipocyte size than control mice although food intake was unchanged. This was associated with increased expression of peroxisome proliferator-activated receptor (PPAR)γ2 and of PPAR-sensitive genes (aP2, adiponectin, leptin, glut-1) in subcutaneous white adipose tissue, as well as in an increased tolerance to glucose. These results show that adipose-ATX is a negative regulator of fat mass expansion in response to an HFD and contributes to plasma LPA levels.
Published: 2011
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217. Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination

Author: Emilie Dejean, Hélène Tronchère, A Colomba, K Thornber, Sylvie Giuriato, Bernard Payrastre, Fabienne Meggetto, Georges Delsol, Frédérique Gaits-Iacovoni, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Simon, Marie Francoise
Subjects: p38 mitogen-activated protein kinases, GTPase, dissemination, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Protein kinase B, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, NPM–ALK, 0303 health sciences, Oncogene, integumentary system, Kinase, business.industry, Hematology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Lymphoma, Oncology, 030220 oncology & carcinogenesis, Invadopodia, Immunology, Cancer research, Original Article, Rac1 GTPase, anaplastic lymphomas, business, Tyrosine kinase
Abstract: International audience; Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM-ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM-ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM-ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas.
Published: 2011
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218. Lysophosphatidic acid-1-receptor targeting agents for fibrosis

Author: Jean-Philippe Pradere, Philippe Valet, Julie Klein, Jean-Sébastien Saulnier-Blache, Joost P. Schanstra, Chloé Rancoule, Jean-Loup Bascands, Julien Gonzalez, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of medicine, Columbia University [New York]-College of Physicians and Surgeons, and Simon, Marie Francoise
Subjects: Cirrhosis, MESH: Clinical Trials as Topic, receptor, Bioinformatics, MESH: Lysophospholipids, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mediator, Fibrosis, Diabetes mellitus, Lysophosphatidic acid, MESH: Molecular Targeted Therapy, medicine, MESH: Receptors, Lysophosphatidic Acid, Animals, Humans, Pharmacology (medical), MESH: Animals, Molecular Targeted Therapy, Receptors, Lysophosphatidic Acid, Receptor, 030304 developmental biology, Pharmacology, 0303 health sciences, Kidney, Clinical Trials as Topic, MESH: Humans, business.industry, fibrosis, antagonist, General Medicine, medicine.disease, 3. Good health, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Immunology, Knockout mouse, MESH: Fibrosis, Lysophospholipids, business, lysophosphatidic acid
Abstract: International audience; INTRODUCTION: The presence of fibrosis is associated with alterations in organ architecture and is responsible for the morbidity of diseases including pneumopathies, systemic sclerosis, liver cirrhosis, chronic cardiovascular diseases, progressive kidney diseases and diabetes. Although a growing number of pro-fibrotic molecules, mediators and other pathways have been reported, there are currently very few antifibrotic molecules being evaluated in clinical trials. AREAS COVERED: Current knowledge about the contribution of lysophosphatidic acid (LPA), a bioactive mediator acting via specific G-protein coupled receptors (LPAR), in the etiology of fibrosis. In a number of organs, fibrosis is associated with increased LPA production as well as with increased expression of some LPAR subtypes (mainly LPA1R). LPAR(-/-) knockout mice and treatment of animal models with specific antagonists clearly demonstrate the contribution of LPA1R subtype to the development of kidney, lung, vascular and dermal fibrosis. The involvement of LPA in liver fibrosis is also strongly suspected but still unproven. EXPERT OPINION: Experiments in animal models clearly demonstrate that LPA1R antagonists have interesting anti-fibrotic potencies. This reveals promising perspectives for the design of new therapeutic approaches to prevent fibrosis-associated diseases. Nevertheless, the number of efficient LPA1R antagonists currently available is still low, and none of them has been used in clinical trials so far.
Published: 2011
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219. Renal tubular fluid shear stress promotes endothelial cell activation

Author: Christiane Pecher, Mathieu Miravète, Muriel Mercier-Bonin, Julie Klein, Joost P. Schanstra, Bénédicte Buffin-Meyer, Aurèle Besse-Patin, Jean-Loup Bascands, Julien Gonzalez, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, and Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Inflammation, Chemokine, Tubular fluid, 030232 urology & nephrology, Urine, MESH: Monocytes, Biochemistry, Monocytes, MESH: Urine, 0302 clinical medicine, MESH: Endothelial Cells, Chemokine CCL2, 0303 health sciences, Kidney, MESH: Stress, Mechanical, biology, MESH: Culture Media, Conditioned, Endothelial stem cell, medicine.anatomical_structure, Kidney Tubules, MESH: Kidney Tubules, Tumor necrosis factor alpha, Kidney Diseases, MESH: Shear Strength, medicine.symptom, Shear Strength, medicine.medical_specialty, Biophysics, Vascular Cell Adhesion Molecule-1, Inflammation, CCL2, MESH: Cell Adhesion, 03 medical and health sciences, Internal medicine, medicine, Cell Adhesion, Humans, Autocrine signalling, Molecular Biology, MESH: Chemokine CCL2, 030304 developmental biology, MESH: Kidney Diseases, MESH: Humans, Tumor Necrosis Factor-alpha, MESH: Vascular Cell Adhesion Molecule-1, Endothelial Cells, Cell Biology, Endocrinology, Culture Media, Conditioned, MESH: Tumor Necrosis Factor-alpha, Immunology, biology.protein, Stress, Mechanical
Abstract: International audience; Modified urinary fluid shear stress (FSS) induced by variations of urinary fluid flow and composition is observed in early phases of most kidney diseases. In this study, we hypothesized that changes in urinary FSS represent a tubular aggression that contributes to the development of inflammation, a key event in progression of nephropathies. Human renal tubular cells (HK-2) were exposed to FSS for 30 min at 0.01 Pa. Treatment of human endothelial cells (HMEC-1) with the resulting conditioned medium (FSS-CM) increased C-C chemokine ligand 2 (CCL2) and tumor necrosis factor (TNF)-α protein secretion, increased endothelial vascular adhesion molecule-1 (VCAM-1) mRNA expression and stimulated adhesion of human (THP-1) monocytes to the endothelial monolayer. These effects were TNF-α dependent as they were abolished by neutralization of TNF-α. Interestingly, the origin of TNF-α was not epithelial, but resulted from autocrine endothelial production. However, in contrast to short term FSS, long term FSS (5h) induced the release of the key inflammatory proteins CCL2 and TNF-α directly from tubular cells. In conclusion, these results suggest for the first time that urinary FSS can contribute to the inflammatory state involved in initiation/perpetuation of renal diseases.
Published: 2011
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220. Immune cells in adipose tissue: Key players in metabolic disorders

Author: Anne Bouloumié, Karine Lolmède, C. Duffaut, Alexia Zakaroff-Girard, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: medicine.medical_specialty, Chemokine, Endocrinology, Diabetes and Metabolism, Adipose tissue macrophages, medicine.medical_treatment, Adipokine, Adipose tissue, 030209 endocrinology & metabolism, Inflammation, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Immune system, Insulin resistance, Adipokines, Metabolic Diseases, Internal medicine, Internal Medicine, medicine, Animals, Humans, Lymphocytes, Obesity, 030304 developmental biology, 0303 health sciences, biology, Dendritic Cells, General Medicine, medicine.disease, 3. Good health, Cytokine, Adipose Tissue, Immunology, biology.protein, medicine.symptom
Abstract: International audience; Obesity, defined as the excess development of adipose tissue, is an important risk factor for metabolic and cardiovascular diseases such as type 2 diabetes, hypertension and atherosclerosis. Over the past few years, metabolic inflammation has emerged as a major process underlying the link between obesity and its associated pathologies. Adipose tissue appears to play a primary and crucial role as a source and site of inflammation. Accumulation of immune cells within adipose tissue occurs in obese conditions. The present review focuses on the relationship between adipose tissue and immune cells, including macrophages, dendritic cells, T and B lymphocytes, and natural killer cells, in both the physiological state and under obese conditions. The factors involved in the accumulation of both myeloid and lymphoid cells in adipose tissue are also described. In addition, the role of adipose-tissue immune cells on adipocyte metabolism and cells of the adipose tissue stromal-vascular fraction are discussed, with particular emphasis on the cross-talk between macrophages and adipocytes, together with recent reports of T lymphocytes in adipose tissue.
Published: 2011
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221. Macrophage gene expression is related to obesity and the metabolic syndrome in human subcutaneous fat as well as in visceral fat

Author: Pauline Decaunes, Balbine Roussel, Jean-José Maoret, Marion Combes, Michaela Siklova-Vitkova, Nathalie Viguerie, Anne Bouloumié, T Vedral, Zuzana Kovacova, Jindra Hejnova, Dominique Langin, Virginie Bourlier, Michaela Kovacikova, Vladimir Stich, Eva Klimcakova, Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of surgery, University Hospital Kralovské Vinohrady, and Simon, Marie Francoise
Subjects: Macrophage, Endocrinology, Diabetes and Metabolism, Adipose tissue, Overweight, 0302 clinical medicine, MESH: Metabolic Syndrome X, Gene expression, MESH: Obesity, Visceral fat, Cells, Cultured, 2. Zero hunger, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Middle Aged, Metabolic syndrome, Real-time polymerase chain reaction, Adipose Tissue, MESH: Young Adult, Female, medicine.symptom, MESH: Adipose Tissue, MESH: Cells, Cultured, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Intra-Abdominal Fat, Biology, Young Adult, 03 medical and health sciences, Insulin resistance, MESH: Subcutaneous Fat, Internal medicine, Diabetes mellitus, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internal Medicine, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, MESH: Overweight, MESH: Intra-Abdominal Fat, Aged, 030304 developmental biology, Inflammation, MESH: Humans, Macrophages, Subcutaneous fat, nutritional and metabolic diseases, MESH: Macrophages, MESH: Adult, medicine.disease, Human adipose tissue, Endocrinology, MESH: Female
Abstract: International audience; AIMS/HYPOTHESIS: Our goal was to identify a set of human adipose tissue macrophage (ATM)-specific markers and investigate whether their gene expression in subcutaneous adipose tissue (SAT) as well as in visceral adipose tissue (VAT) is related to obesity and to the occurrence of the metabolic syndrome. METHODS: ATM-specific markers were identified by DNA microarray analysis of adipose tissue cell types isolated from SAT of lean and obese individuals. We then analysed gene expression of these markers by reverse transcription quantitative PCR in paired samples of SAT and VAT from 53 women stratified into four groups (lean, overweight, obese and obese with the metabolic syndrome). Anthropometric measurements, euglycaemic-hyperinsulinaemic clamp, blood analysis and computed tomography scans were performed. RESULTS: A panel of 24 genes was selected as ATM-specific markers based on overexpression in ATM compared with other adipose tissue cell types. In SAT and VAT, gene expression of ATM markers was lowest in lean and highest in the metabolic syndrome group. mRNA levels in the two fat depots were negatively correlated with glucose disposal rate and positively associated with indices of adiposity and the metabolic syndrome. CONCLUSIONS/INTERPRETATION: In humans, expression of ATM-specific genes increases with the degree of adiposity and correlates with markers of insulin resistance and the metabolic syndrome to a similar degree in SAT and in VAT.
Published: 2011
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222. Deciphering biased-agonism complexity reveals a new active AT1 receptor entity

Author: Morgane Bellot, Frédéric Finana, Jean-Michel Senard, Marie-Hélène Seguelas, Aude Saulière, Marie-Françoise Altié, Céline Galés, Jonas Tind Hansen, Jakob Lerche Hansen, Atul Pathak, Colette Denis, Hervé Paris, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie cellulaire et moléculaire, Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE-PIERRE FABRE, Laboratory for Molecular Cardiology, Danish National Research Foundation Centre for Cardiac Arrhythmia-University of Copenhagen = Københavns Universitet (KU), Laboratoire de pharmacologie médicale et clinique, CHU Toulouse [Toulouse], Simon, Marie Francoise, Danish National Research Foundation Centre for Cardiac Arrhythmia-University of Copenhagen = Københavns Universitet (UCPH), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Agonist, MESH: GTP-Binding Proteins, G protein, medicine.drug_class, Protein Conformation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biosensing Techniques, Biology, Receptor, Angiotensin, Type 1, Cell Line, 03 medical and health sciences, 0302 clinical medicine, MESH: Protein Conformation, GTP-Binding Proteins, Functional selectivity, medicine, Humans, 5-HT5A receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, 030304 developmental biology, G protein-coupled receptor, 0303 health sciences, G protein-coupled receptor kinase, Angiotensin II receptor type 1, MESH: Humans, Cell Biology, Angiotensin II, Cell biology, MESH: Cell Line, Biochemistry, MESH: Receptor, Angiotensin, Type 1, 030217 neurology & neurosurgery, MESH: Biosensing Techniques
Abstract: International audience; Functional selectivity of G protein-coupled receptor (GPCR) ligands toward different downstream signals has recently emerged as a general hallmark of this receptor class. However, pleiotropic and crosstalk signaling of GPCRs makes functional selectivity difficult to decode. To look from the initial active receptor point of view, we developed new, highly sensitive and direct bioluminescence resonance energy transfer-based G protein activation probes specific for all G protein isoforms, and we used them to evaluate the G protein-coupling activity of [(1)Sar(4)Ile(8)Ile]-angiotensin II (SII), previously described as an angiotensin II type 1 (AT(1)) receptor-biased agonist that is G protein independent but β-arrestin selective. By multiplexing assays sensing sequential signaling events, from receptor conformations to downstream signaling, we decoded SII as an agonist stabilizing a G protein-dependent AT(1A) receptor signaling module different from that of the physiological agonist angiotensin II, both in recombinant and primary cells. Thus, a biased agonist does not necessarily select effects from the physiological agonist but may instead stabilize and create a new distinct active pharmacological receptor entity.
Published: 2011
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223. Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice

Author: Patrice D. Cani, Marco Peters, Dominic J. Withers, Rachel L. Batterham, Alan Ashworth, Claude Knauf, Anne White, Rémy Burcelin, Philippe Valet, André Colom, Kaisa Piipari, Hind Al-Qassab, Angela Woods, K. Peter Giese, Ghazala Begum, Amanda Heslegrave, Michael L.J. Ashford, Mark A. Smith, Marc Claret, Keiko Mizuno, Phillip Mucket, David Carling, Julian J. Emmanuel, Laboratory of Diabetes and Obesity, Endocrinology and Nutrition Unit, Hospital Clínic de Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Metabolic Signalling Group, Imperial College London-Clinical Sciences Centre-Medical Research Council (MRC), Biomedical Research Institute, University of Dundee-Ninewells Hospital and Medical School [Dundee], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellular Stress Group, Centre for Diabetes and Endocrinology, University College of London [London] (UCL)-Rayne Institute, Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Louvain Drug Research Institute, Manchester Academic Health Sciences Centre, University of Manchester [Manchester]-Faculties of Life Sciences and Medical and Human Sciences, Centre for the Cellular Basis of Behaviour, Institute of psychiatry-King‘s College London, The Breakthrough Breast Cancer Research Centre, Institute of cancer research, This work was supported by grants from the Biotechnology and Biological Sciences Research Council (to D.J.W.), the Medical Research Council (to D.J.W., R.L.B., K.P.G., and D.C.), the Wellcome Trust (to D.J.W., K.P.G., and M.L.A.), and the European Commission (contract no. LSHM-CT-2004-005272, to D.C.). M.C. is a recipient of a Miguel Servet contract (CP09/00233) from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (Spain)., UCL - SSS/LDRI - Louvain Drug Research Institute, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Male, MESH: Signal Transduction, Pro-Opiomelanocortin, Endocrinology, Diabetes and Metabolism, MESH: Neurons, Cell Count, AMP-Activated Protein Kinases, MESH: Glucose Clamp Technique, MESH: Eating, Energy homeostasis, Mice, Eating, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Glucose homeostasis, Homeostasis, MESH: Pro-Opiomelanocortin, MESH: Animals, Neurons, 0303 health sciences, MESH: Statistics, Nonparametric, MESH: Electrophysiology, Reverse Transcriptase Polymerase Chain Reaction, digestive, oral, and skin physiology, MESH: Energy Metabolism, Glucose clamp technique, Protein-Serine-Threonine Kinases, Immunohistochemistry, Electrophysiology, MESH: Glucose, MESH: Insulin Resistance, MESH: Homeostasis, Area Under Curve, Female, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, medicine.medical_specialty, endocrine system, MESH: Mice, Transgenic, Hypothalamus, Mice, Transgenic, Protein Serine-Threonine Kinases, Carbohydrate metabolism, Biology, Statistics, Nonparametric, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, Insulin resistance, Internal medicine, MESH: Analysis of Variance, Internal Medicine, medicine, Animals, Protein kinase A, MESH: Mice, 030304 developmental biology, Analysis of Variance, MESH: Cell Count, Body Weight, AMPK, MESH: Immunohistochemistry, medicine.disease, MESH: Hypothalamus, MESH: Male, MESH: Body Weight, Metabolism, Endocrinology, Glucose, nervous system, Glucose Clamp Technique, MESH: Area Under Curve, Insulin Resistance, Energy Metabolism, MESH: Female, 030217 neurology & neurosurgery
Abstract: OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin–dependent protein kinase kinase β (CaMKKβ) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS Mice lacking either Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS Deletion of Camkkβ in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte–stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons.
Published: 2011
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224. Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists

Author: Chantal Escrieut, Bernard Masri, Magali Foucaud, Remi Magnan, Pierre Cordelier, Daniel Fourmy, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Arrestins, [SDV]Life Sciences [q-bio], MESH: Gastrins, Biochemistry, 0302 clinical medicine, MESH: Cholecystokinin, Phosphorylation, Internalization, Receptor, Inositol phosphate, beta-Arrestins, media_common, chemistry.chemical_classification, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Endocytosis, 3. Good health, Cell biology, MESH: HEK293 Cells, Cholecystokinin B receptor, MESH: Endocytosis, MESH: Arrestins, Cholecystokinin, MESH: Mitogen-Activated Protein Kinase 3, MESH: Mitogen-Activated Protein Kinase 1, Signal Transduction, Endosome, media_common.quotation_subject, education, Endosomes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Receptor, Cholecystokinin B, 03 medical and health sciences, Gastrins, Humans, Molecular Biology, 030304 developmental biology, Dynamin, MESH: Humans, MESH: Phosphorylation, Beta-Arrestins, Cell Biology, Receptor, Cholecystokinin B, HEK293 Cells, chemistry, MESH: Endosomes, Lysosomes, 030217 neurology & neurosurgery, MESH: Lysosomes
Abstract: International audience; Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R*β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.
Published: 2011
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225. Timing of the vascular actions of estrogens in experimental and human studies: why protective early, and not when delayed?

Author: Jean-François Arnal, Françoise Lenfant, Pierre Gourdy, Florence Trémollières, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: MESH: Menopause, medicine.medical_treatment, Estrogen receptor, Coronary Disease, 030204 cardiovascular system & hematology, Bioinformatics, MESH: Estrogens, MESH: Atherosclerosis, 0302 clinical medicine, Medroxyprogesterone acetate, MESH: Animals, 0303 health sciences, Estradiol, Human studies, Obstetrics and Gynecology, Plaque, Atherosclerotic, 3. Good health, Menopause, Receptors, Estrogen, Preventive action, MESH: Receptors, Estrogen, Female, MESH: Endothelium, Vascular, MESH: Estradiol, hormones, hormone substitutes, and hormone antagonists, medicine.drug, medicine.medical_specialty, medicine.drug_class, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, MESH: Plaque, Atherosclerotic, 030304 developmental biology, MESH: Humans, business.industry, Estrogens, Atherosclerosis, medicine.disease, Endocrinology, Estrogen, MESH: Progestins, Endothelium, Vascular, Hormone therapy, MESH: Coronary Disease, Progestins, business, MESH: Female, Hormone
Abstract: International audience; Estrogens, and in particular 17β-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes including the cardiovascular system. Although epidemiological studies and Nurses' Health Study suggested, and all animal models of early atheroma clearly demonstrated a vasculoprotective action of both endogenous and exogenous estrogens, the Women's Health Initiative did not confirm the preventive action of estrogens against coronary heart disease (CHD). However, women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with increased CHD risk among women more distant from menopause. Thus, it is now mandatory to try to understand the mechanisms that could have influenced the actions of estrogens at various stages of atherosclerosis and/or of life. In this current review, we will summarize our understanding of the potential cellular targets and mechanisms of the vasculoprotective actions of estrogens, as well as of the lack of action of estrogens when administered after a period of hormonal deprivation. The mechanisms of the aggravating role of progestogens such as medroxyprogesterone acetate will be considered. Finally, we will analyze the possibilities to uncouple some beneficial from other undesirable actions following the partial/selective activation of estrogen receptors.
Published: 2011
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226. The gut-brain axis: a major glucoregulatory player

Author: Rémy Burcelin, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: MESH: Signal Transduction, medicine.medical_specialty, MESH: Diabetes Mellitus, Endocrinology, Diabetes and Metabolism, Gut–brain axis, Central nervous system, Incretin, Carbohydrate metabolism, Biology, Autonomic Nervous System, MESH: Incretins, Incretins, MESH: Autonomic Nervous System, MESH: Brain, Endocrinology, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Diabetes Mellitus, Glucose homeostasis, Animals, Humans, MESH: Animals, MESH: Humans, Brain, General Medicine, medicine.disease, MESH: Glucose, Intestines, Autonomic nervous system, medicine.anatomical_structure, Glucose, Reflex, MESH: Intestines, Signal Transduction
Abstract: International audience; Glucose homeostasis corresponds to the overall physiological, cellular, and molecular mechanisms which tightly maintain the glycaemia between ∼4.5 and ∼6 mM. The resulting blood glucose concentration is the consequence of a balance between the mechanisms that ensure the entry and the output of glucose in the blood. A dynamic balance needs hence to be perfectly achieved in order to maintain a physiological glycaemic concentration. Specialized cells from the intestine continuously detect changes in glucose concentration and send signals to peripheral tissues and the brain through the vagus nerve. The molecular mechanisms involved in glucose detection have not been perfectly defined but could resemble those from the insulin-secreting beta cells. The brain then integrates the enteric and circulating endocrine signals to generate a new signal towards peripheral tissues such as the pancreas, liver, muscles, and blood vessels. This metabolic reflex is called anticipatory since it allows the peripheral tissues to prepare for the adequate handling of nutrients. Diabetes is associated with an impaired anticipatory reflex, which hampers the proper detection of nutrients and leads to hyperglycaemic episodes. Recently, GLP-1-based therapies have demonstrated the improvement of glucose detection and their efficacy on glycaemic control. Although not yet fully demonstrated, GLP-1-based therapies regulate glucose sensors, which leads to the glycaemic improvement. Certainly other molecular targets could be identified to further generate new therapeutic strategies.
Published: 2011
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227. The NPM-ALK oncogene interacts, activates and uses PIKfyve to increase invasiveness

Author: Dupuis-Coronas, Sophie, Lagarrigue, Frederic, Ramel, Damien, Chicanne, Gaetan, Saland, Estelle, Gaits-Iacovoni, Frederique, Payrastre, Bernard, Tronchere, Helene, Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire d'Hématologie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]
Subjects: integumentary system, hemic and lymphatic diseases
Abstract: International audience; NPM-ALK is a chimeric tyrosine kinase detected in most anaplastic large cell lymphomas which results from the reciprocal translocation t(2,5)(p23;q35) that fuses the N-terminal domain of nucleophosmin (NPM) to the catalytic domain of the ALK receptor. The constitutive activity of the kinase is responsible for its oncogenicity through the stimulation of several downstream signaling pathways leading to cell proliferation, migration and survival. We previously demonstrated that the high level of phosphatidylinositol 5-phosphate (PtdIns5P) measured in NPM-ALK expressing cells is controlled by the phosphoinositide kinase PIKfyve, a lipid kinase known for its role in vesicular trafficking. Here, we show that PIKfyve associates with NPM-ALK and that the interaction involves the 181-300 region of the oncogene. Moreover, we demonstrate that the tyrosine kinase activity of the oncogene controls PIKfyve lipid kinase activity, but is dispensable for the formation of the complex. Silencing or inhibition of PIKfyve, by using siRNA or the PIKfyve inhibitor YM201636, have no effect on NPM-ALK-mediated proliferation and migration, but strongly reduce invasive capacities of NPM-ALK expressing cells and their capacity to degrade the extracellular matrix. Accordingly, immunofluorescence studies confirm a perturbation of MMP-9 localization at the cell surface and defect in maturation. Altogether, these results suggest a role for PIKfyve in NPM-ALK mediated invasion.
Published: 2011
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228. A distinct adipose tissue gene expression response to caloric restriction predicts 6-mo weight maintenance in obese subjects

Author: Claus Holst, M. Ramzi Temanni, Marleen A. van Baak, Véronique Pelloux, Celia G. Walker, Dominique Langin, Teodora Handjieva-Darlenska, Dimitris K. Babalis, Arne Astrup, Jean-Daniel Zucker, Karine Clément, J. Alfredo Martínez, David M. Mutch, Wim H. M. Saris, Adriana Márquez-Quiñones, Tune H. Pers, Nathalie Viguerie, Simon, Marie Francoise, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Health and Nutritional Sciences, University of Guelph, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Institute of Preventive Medicine, Copenhagen University Hospital, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Fédératif de Recherche Bio-médicale Institution (IFR150), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), the Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Internal Medicine, University Hospital of Heraklion, Nutrition Research Centre (NUTRIM), Maastricht University [Maastricht], National Multiprofile Transport Hospital, Human Nutrition Research, Medical Research Council, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technical University of Denmark [Lyngby] ( DTU ), Service Nutrition, Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut Français pour la Nutrition - IFN-Centre de Recherche en Nutrition Humaine - CRNH-Ile de France-CHU Pitié-Salpêtrière [APHP], Institut Fédératif de Recherche Bio-médicale, Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-IFR 150, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Universidad de Navarra [Pamplona] ( UNAV ), Nutrition Research Centre ( NUTRIM ), Faculty of Life Sciences-University of Copenhagen ( KU ), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technical University of Denmark [Lyngby] (DTU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-IFR150, and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)
Subjects: Weight loss, Calorie, medicine.medical_treatment, MESH : Insulin, [SDV]Life Sciences [q-bio], Gene Expression, Medicine (miscellaneous), Adipose tissue, PROTEIN, REGAIN, MESH : Analysis of Variance, Weight Gain, 0302 clinical medicine, Insulin Secretion, Insulin, MESH: Obesity, MESH : Female, 0303 health sciences, Glucose tolerance test, Nutrition and Dietetics, MESH: Middle Aged, medicine.diagnostic_test, MESH : Gene Expression Regulation, MESH : Weight Gain, Middle Aged, MESH : Adult, MESH: Gene Expression Regulation, [SDV] Life Sciences [q-bio], BODY-WEIGHT, Gene xxpression, MESH : Subcutaneous Fat, MESH: Young Adult, MESH: Weight Gain, DIETS, Female, MESH : Obesity, medicine.symptom, SENSITIVITY, INTERVENTIONS, Adult, medicine.medical_specialty, MESH : Caloric Restriction, MESH: Gene Expression, MESH: Glucose Tolerance Test, Caloric restriction, Subcutaneous Fat, MESH : Young Adult, 030209 endocrinology & metabolism, MESH: Insulin, Biology, INSULIN-SECRETION, MESH : Glucose Tolerance Test, Young Adult, 03 medical and health sciences, MESH: Weight Loss, MESH: Subcutaneous Fat, Internal medicine, Diabetes mellitus, MESH: Analysis of Variance, Weight Loss, medicine, EXTRACELLULAR-MATRIX, Humans, MESH : Middle Aged, Obesity, Weight gain, Caloric Restriction, 030304 developmental biology, Analysis of Variance, MESH: Caloric Restriction, MESH: Humans, MESH : Humans, MESH: Adult, Glucose Tolerance Test, medicine.disease, MESH : Gene Expression, ENERGY-INTAKE, Endocrinology, Gene Expression Regulation, MESH : Weight Loss, GAIN, MESH: Female
Abstract: Background: Weight loss has been shown to reduce risk factors associated with cardiovascular disease and diabetes; however, successful maintenance of weight loss continues to pose a challenge. Objective: The present study was designed to assess whether changes in subcutaneous adipose tissue (scAT) gene expression during a low-calorie diet (LCD) could be used to differentiate and predict subjects who experience successful short-term weight maintenance from subjects who experience weight regain. Design: Forty white women followed a dietary protocol consisting of an 8-wk LCD phase followed by a 6-mo weight-maintenance phase. Participants were classified as weight maintainers (WMs; 0‐10% weight regain) and weight regainers (WRs; 50‐100% weight regain) by considering changes in body weight during the 2 phases. Anthropometric measurements, bioclinical variables, and scAT gene expression were studied in all individuals before and after the LCD. Energy intake was estimated by using 3-d dietary records. Results: No differences in body weight and fasting insulin were observed between WMs and WRs at baseline or after the LCD period. The LCD resulted in significant decreases in body weight and in several plasma variables in both groups. WMs experienced a significant reduction in insulin secretion in response to an oralglucose-tolerance test after the LCD; in contrast, no changes in insulin secretion were observed in WRs after the LCD. An ANOVA of scAT gene expression showed that genes regulating fatty acid metabolism, citric acid cycle, oxidative phosphorylation, and apoptosis were regulated differently by the LCD in WM and WR subjects. Conclusion: This study suggests that LCD-induced changes in insulin secretion and scAT gene expression may have the potential to predict successful short-term weight maintenance. This trial was registered at clinicaltrials.gov as NCT00390637. Am J Clin Nutr 2011;94:1399‐409.
Published: 2011
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229. Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control

Author: Laurent Pechere, Aurélie Waget, Rémy Burcelin, Yves Barra, Serge Champion, Eric Seree, Matteo Serino, Christelle Vachoux, Thi-Mai Anh Dao, Pascale Klopp, Sylvain Barthélemy, Daniel J. Drucker, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutriments Lipidiques et Prévention des Maladies Métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université de la Méditerranée - Aix-Marseille 2, Incubateur Midi-Pyrennées, ENTERONOVA SAS, Department of Medicine, University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital [Toronto, Canada] (MSH), YVERY SARL, Rémy Burcelin is the recipient of subsidies from the Agence Nationale de la Recherche (Program Brain GLP-1). This manuscript was partly funded by a grant (IISP program) from Merck Sharp and Dohm to RB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Toronto-Mount Sinai Hospital (MSH)-Samuel Lunenfeld Research Institute, Simon, Marie Francoise, and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Blood Glucose, Male, Anatomy and Physiology, Time Factors, medicine.medical_treatment, Resveratrol, MITOCHONDRIAL-FUNCTION, chemistry.chemical_compound, Mice, 0302 clinical medicine, Glucagon-Like Peptide 1, Stilbenes, Receptors, Glucagon, 0303 health sciences, INSULIN-RESISTANCE, Multidisciplinary, GLUCAGON-LIKE PEPTIDE-1, Chemistry, digestive, oral, and skin physiology, Proglucagon, Glucagon-like peptide-1, 3. Good health, Intestines, Sitagliptin, OBESITY, Medicine, medicine.drug, Research Article, EXPRESSION, medicine.medical_specialty, Science, Dipeptidyl Peptidase 4, PGC-1-ALPHA, Immunology, 030209 endocrinology & metabolism, Endocrine System, Gastroenterology and Hepatology, SIRT1, DIET, INFLAMMATION, ENDOTOXEMIA, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, Insulin resistance, Diabetes mellitus, Internal medicine, Glucose Intolerance, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biology, Dipeptidyl peptidase-4, 030304 developmental biology, Diabetic Endocrinology, Dipeptidyl-Peptidase IV Inhibitors, Insulin, Immunity, medicine.disease, Dietary Fats, Mice, Inbred C57BL, Endocrinology, Metagenome
Abstract: International audience; Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.
Published: 2011
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230. Brain GLP-1 Signaling Regulates Femoral Artery Blood Flow and Insulin Sensitivity Through Hypothalamic PKC-{delta}

Author: Christelle Vachoux, Daniel J. Drucker, Rémy Burcelin, Cendrine Cabou, Gérard Campistron, Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie, Faculté de Pharmacie de Toulouse, Department of Medicine, and University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital [Toronto, Canada] (MSH)
Subjects: Male, medicine.medical_specialty, endocrine system, Endocrinology, Diabetes and Metabolism, Glucose uptake, medicine.medical_treatment, Hypothalamus, Femoral artery, Biology, Glucagon-Like Peptide-1 Receptor, Mice, 03 medical and health sciences, 0302 clinical medicine, Glucagon-Like Peptide 1, Internal medicine, medicine.artery, Receptors, Glucagon, Internal Medicine, medicine, Animals, Hypoglycemic Agents, Insulin, Receptor, Protein kinase C, 030304 developmental biology, Mice, Knockout, 2. Zero hunger, 0303 health sciences, Venoms, digestive, oral, and skin physiology, Brain, Glucagon-like peptide-1, Femoral Artery, Protein Kinase C-delta, Metabolism, Endocrinology, Regional Blood Flow, Exenatide, Signal transduction, Peptides, 030217 neurology & neurosurgery, Signal Transduction, Hormone
Abstract: OBJECTIVE Glucagon-like peptide 1 (GLP-1) is a gut-brain hormone that regulates food intake, energy metabolism, and cardiovascular functions. In the brain, through a currently unknown molecular mechanism, it simultaneously reduces femoral artery blood flow and muscle glucose uptake. By analogy to pancreatic β-cells where GLP-1 activates protein kinase C (PKC) to stimulate insulin secretion, we postulated that PKC enzymes would be molecular targets of brain GLP-1 signaling that regulate metabolic and vascular function. RESEARCH DESIGN AND METHODS We used both genetic and pharmacological approaches to investigate the role of PKC isoforms in brain GLP-1 signaling in the conscious, free-moving mouse simultaneous with metabolic and vascular measurements. RESULTS In normal wild-type (WT) mouse brain, the GLP-1 receptor (GLP-1R) agonist exendin-4 selectively promotes translocation of PKC-δ (but not -βII, -α, or -ε) to the plasma membrane. This translocation is blocked in Glp1r−/− mice and in WT mice infused in the brain with exendin-9, an antagonist of the GLP-1R. This mechanism coordinates both blood flow in the femoral artery and whole-body insulin sensitivity. Consequently, in hyperglycemic, high-fat diet–fed diabetic mice, hypothalamic PKC-δ activity was increased and its pharmacological inhibition improved both insulin-sensitive metabolic and vascular phenotypes. CONCLUSIONS Our studies show that brain GLP-1 signaling activates hypothalamic glucose-dependent PKC-δ to regulate femoral artery blood flow and insulin sensitivity. This mechanism is attenuated during the development of experimental hyperglycemia and may contribute to the pathophysiology of type 2 diabetes.
Published: 2011
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231. Oxidized LDLs trigger endoplasmic reticulum stress and autophagy: prevention by HDLs

Author: Robert Salvayre, Cécile Vindis, Carole Muller, Anne Nègre-Salvayre, Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Biology, Models, Biological, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Autophagy, Animals, Humans, Molecular Biology, Drug Antagonism, 030304 developmental biology, 0303 health sciences, Endoplasmic reticulum, Cell Biology, Endoplasmic Reticulum Stress, 3. Good health, Cell biology, Lipoproteins, LDL, Apoptosis, 030220 oncology & carcinogenesis, Unfolded protein response, lipids (amino acids, peptides, and proteins), Lipoproteins, HDL, Signal Transduction
Abstract: International audience; Oxidized LDLs (oxLDLs) induce various cellular dysfunctions potentially implicated in the pathogenesis of atherosclerosis. For instance, toxic concentrations of oxLDLs trigger ER stress, autophagy and apoptosis. High-density lipoproteins (HDLs) counteract several adverse biological effects triggered by oxLDLs. Our recent study reveals that HDLs inhibit the activation of ER stress and of autophagy induced by oxLDLs.
Published: 2011

232. GLP-1, the gut-brain, and brain-periphery axes

Author: Cendrine Cabou, Rémy Burcelin, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: medicine.medical_specialty, endocrine system, Endocrinology, Diabetes and Metabolism, Neuropeptide, 030209 endocrinology & metabolism, Review, Biology, 03 medical and health sciences, MESH: Brain, 0302 clinical medicine, Endocrinology, Glucagon-Like Peptide 1, Internal medicine, Diabetes mellitus, Peripheral Nervous System, Internal Medicine, medicine, Animals, Humans, Glucose homeostasis, MESH: Animals, Intestinal Mucosa, Receptor, 030304 developmental biology, MESH: Peripheral Nervous System, 0303 health sciences, MESH: Humans, Area postrema, digestive, oral, and skin physiology, Brain, MESH: Glucagon-Like Peptide 1, medicine.disease, Glucagon-like peptide-1, Diabetes Mellitus, Type 2, Hypothalamus, Neuroscience, hormones, hormone substitutes, and hormone antagonists, Hormone, MESH: Diabetes Mellitus, Type 2, MESH: Intestines
Abstract: International audience; Glucagon-like peptide 1 (GLP-1) is a gut hormone which directly binds to the GLP-1 receptor located at the surface of the pancreatic β-cells to enhance glucose-induced insulin secretion. In addition to its pancreatic effects, GLP-1 can induce metabolic actions by interacting with its receptors expressed on nerve cells in the gut and the brain. GLP-1 can also be considered as a neuropeptide synthesized by neuronal cells in the brain stem that release the peptide directly into the hypothalamus. In this environment, GLP-1 is assumed to control numerous metabolic and cardiovascular functions such as insulin secretion, glucose production and utilization, and arterial blood flow. However, the exact roles of these two locations in the regulation of glucose homeostasis are not well understood. In this review, we highlight the latest experimental data supporting the role of the gut-brain and brain-periphery axes in the control of glucose homeostasis. We also focus our attention on the relevance of β-cell and brain cell targeting by gut GLP-1 for the regulation of glucose homeostasis. In addition to its action on β-cells, we find that understanding the physiological role of GLP-1 will help to develop GLP-1-based therapies to control glycemia in type 2 diabetes by triggering the gut-brain axis or the brain directly. This pleiotropic action of GLP-1 is an important concept that may help to explain the observation that, during their treatment, type 2 diabetic patients can be identified as 'responders' and 'non-responders'.
Published: 2011
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233. Native human adipose stromal cells: localization, morphology and phenotype

Author: Louis Casteilla, Peyrafitte Ja, Philippe Bourin, Marie Maumus, D'Angelo R, Coralie Sengenès, A. Bouloumié, Fournier-Wirth C, Simon, Marie Francoise, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de recherche, Etablissement Français du Sang Pyrénées-Méditerranée, Laboratoire de thérapie cellulaire, This work was supported by the Fondation pour la Recherche Médicale (DCV20070409252, programme Vieillissement Cardiovasculaire Normal et Pathologique), the Région Midi-Pyrénées (programme n°07006299), Communauté de Travail des Pyrénées, programme R9390173, and Appel d'offre Coopération, Recherche - Développement (2007), the Prix de Recherche de l'Association Française d'étude et de recherches sur l'obésité (Aféro) and Roche (2007).
Subjects: Adult, endocrine system, Pathology, medicine.medical_specialty, Stromal cell, Endocrinology, Diabetes and Metabolism, Cellular differentiation, CD34, Medicine (miscellaneous), Adipose tissue, Biology, confocal imaging, Immunophenotyping, medicine, Humans, Obesity, human, Cells, Cultured, Nutrition and Dietetics, Adipogenesis, Reverse Transcriptase Polymerase Chain Reaction, Mesenchymal stem cell, 3T3-L1, hemic and immune systems, Cell Differentiation, Mesenchymal Stem Cells, Flow Cytometry, eye diseases, Cell biology, pericytes endothelial cells, Phenotype, Adipose Tissue, Cell culture, Female, Original Article, Stromal Cells, mesenchymal stromal cells, Biomarkers
Abstract: International audience; Objectives:Beside having roles in energy homeostasis and endocrine modulation, adipose tissue (AT) is now considered a promising source of mesenchymal stromal cells (adipose-derived stromal cells or ASCs) for regenerative medicine. Despite numerous studies on cultured ASCs, native human ASCs are rarely investigated. Indeed, the phenotype of ASCs in their native state, their localization within AT and comparison with bone marrow-derived mesenchymal stromal cells (BM-MSCs) has been poorly investigated.Design:To address these issues, the stroma vascular fraction (SVF) of human AT was extracted and native cell subtypes were isolated by immunoselection to study their clonogenic potential in culture. Immunohistology on samples of human AT in combination with reconstruction of confocal sections were performed in order to localize ASCs.Results:Compared with BM-MNCs, all native ASCs were found in the CD34(+) cell fraction of the AT-SVF. Native ASCs expressed classical mesenchymal markers described for BM-MSCs. Interestingly, CD34 expression decreased during ASC cell culture and was negatively correlated with cell proliferation rate. Immunohistological analysis revealed that native ASCs exhibited specific morphological features with protrusions. They were found scattered in AT stroma and did not express in vivo pericytic markers such as NG2, CD140b or alpha-smooth muscle actin, which appeared during the culture process. Finally, ASCs spontaneous commitment to adipocytic lineage was enhanced in AT from obese humans.Conclusions:The use of complementary methodological approaches to study native human ASCs revealed their immunophenotype, their specific morphology, their location within AT and their stemness. Furthermore, our data strongly suggest that human ASCs participate in adipogenesis during AT development.International Journal of Obesity advance online publication, 25 January 2011; doi:10.1038/ijo.2010.269.
Published: 2011
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234. Neuroprotective properties of GLP-1: theoretical and practical applications

Author: Jens J. Holst, Rémy Burcelin, Esther Nathanson, Simon, Marie Francoise, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Watermeadow Medical USA
Subjects: medicine.medical_specialty, Parkinson's disease, medicine.medical_treatment, Type 2 diabetes, Disease, Models, Biological, Nervous System, Neuroprotection, MESH: Nervous System Diseases, Diabetes Complications, Huntington's disease, Glucagon-Like Peptide 1, Internal medicine, medicine, Animals, Humans, MESH: Animals, MESH: Models, Theoretical, MESH: Humans, MESH: Nervous System, Gastric emptying, business.industry, Insulin, digestive, oral, and skin physiology, MESH: Models, Biological, MESH: Glucagon-Like Peptide 1, General Medicine, MESH: Neuroprotective Agents, Models, Theoretical, medicine.disease, MESH: Diabetes Complications, Autonomic nervous system, Neuroprotective Agents, Endocrinology, Nervous System Diseases, business, Neuroscience
Abstract: International audience; In the past few years, the development of pharmaceutical agents that enhance the physiological effects of glucagon-like peptide-1 (GLP-1), either through GLP-1 receptor agonism (GLP-1 agonists) or by inhibiting GLP-1 degradation (dipeptidylpeptidase-4 inhibitors) has broadened the range of treatment options for individuals with type 2 diabetes. It has been recognized for some time that GLP-1 also has extra-pancreatic effects, notably targeting the brain, where it regulates appetite and satiety, as well as peripheral functions highly controlled by the autonomic nervous system, such as gastric emptying. Furthermore, data are beginning to emerge that indicate a potential role for GLP-1 in neuroprotection. The increased risk of Alzheimer's disease, Parkinson's disease and stroke in people with type 2 diabetes suggests that shared mechanisms/pathways of cell death, possibly related to insulin dysregulation, may underlie all of these disorders. Although the disease anatomy varies with each disorder, a wide range of genetic and environmental triggers result in activation of similar biochemical pathways in all of them, suggesting a complex network of biochemical events that feed in to a final common path towards cellular dysfunction and death. This article summarizes the evidence for neuronal activity of GLP-1 and examines the limited data that currently exist on the therapeutic potential of GLP-1 in specific neurological and neurodegenerative conditions, namely Alzheimer's disease, Parkinson's disease, Huntingdon's disease, stroke and peripheral sensory neuropathy.
Published: 2011
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235. Is Crohn’s creeping fat an adipose tissue?

Author: Jean-Pierre Segain, Laurent Ferrier, Isabelle Olivier, Philippe Valet, Valérie Bézirard, Sylvain Kirzin, Robert Ducroc, Helene Eutamene, J Moreau, Christel Cartier, Justine Bertrand-Michel, Isabelle Castan-Laurell, Jean-Pierre Duffas, Hervé Guillou, Vassilia Theodorou, Guillaume Portier, Eutamene, Hélène, Unité de nutrition et neuro-gastroentérologie, Institut National de la Recherche Agronomique (INRA)-PRES Université de Toulouse-El-Purpan-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique (INRA), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Chirurgie Générale et Digestive [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Chirurgie Générale et Digestive [Rangueil], CHU Toulouse [Toulouse]-Hôpital de Rangueil, Physiologie des Adaptations Nutritionnelles (PhAN), Neuro-Gastroentérologie et Nutrition (NGN), Institut National de la Recherche Agronomique (INRA)-Ecole supérieure d'agriculture de Purpan (ESAP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise
Subjects: Male, Pathology, [SDV]Life Sciences [q-bio], Adipose tissue, Cystic fibrosis, Immunoenzyme Techniques, Mice, 0302 clinical medicine, Crohn Disease, MESH: Peroxidase, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Colitis, Immunology and Allergy, Medicine, MESH: Animals, Mesentery, 0303 health sciences, Crohn's disease, Mice, Inbred BALB C, Reverse Transcriptase Polymerase Chain Reaction, Gastroenterology, MESH: Enzyme-Linked Immunosorbent Assay, Colitis, Lipids, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Adipose Tissue, 030211 gastroenterology & hepatology, medicine.symptom, MESH: Adipose Tissue, MESH: Dinitrofluorobenzene, medicine.medical_specialty, Blotting, Western, MESH: Mice, Inbred BALB C, creeping fat, mesenteric adipose tissue, Crohn’s disease, animal model, Inflammation, Enzyme-Linked Immunosorbent Assay, 03 medical and health sciences, Animal model, MESH: Blotting, Western, Animals, Humans, RNA, Messenger, MESH: Immunoenzyme Techniques, MESH: Mesentery, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Peroxidase, MESH: Humans, MESH: Crohn Disease, business.industry, Body Weight, medicine.disease, MESH: Lipids, MESH: Male, MESH: Body Weight, Mesenteric adipose tissue, Dinitrofluorobenzene, business, Human Pathology
Abstract: International audience; BACKGROUND: In human pathology, the "creeping fat" (CF) of the mesentery is unique to Crohn's disease (CD). CF is usually referred to as an ectopic extension of mesenteric adipose tissue (MAT). However, since no animal model developing CF has ever been established, very little is known about this type of fat-depot expansion and its role in the development of the disease. METHODS: We developed and standardized an experimental protocol in mice that reproducibly induces CF development when a severe colonic inflammation is obtained by intracolonic instillation of DNBS. RESULTS: Macro-microscopic observations revealed a fatty appearance of CF. Yet when compared to MAT from the same animals, CF contains very little triglycerides, few adipocytes, and we observed a very low expression and protein levels of both adipose markers (hormone-sensitive lipase, perilipin) and adipocytokines (leptin, adiponectin). The decreased expression of perilipin in CF was also observed by immunohistochemistry. Conversely, the expression of proinflammatory and fibrous markers (Pref-1) was much higher in CF than in MAT. These observations were fully consistent with those made on CF recovered from five CD patients and compared with subcutaneous and mesenteric fat from the same patients. CONCLUSIONS: Altogether, this work reports an original experimental mice model of CF. In this model we establish for the first time that CF only occurs in severe colonic inflammation and shows an inflammatory, fibrous but not an adipose pattern.
Published: 2011
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236. Blood signature of pre-heart failure: a microarrays study

Author: Fatima Smih, Michel Galinier, Romain Harmancey, Charlotte Trouillet, Olivier Lairez, Pierre Massabuau, Clément Delmas, Annie Turkieh, Matthieu Berry, Jean Ferrières, Atul Pathak, Jason S. Iacovoni, Franck Desmoulin, Philippe Rouet, François Koukoui, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie [Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], This work was supported by the National Research Agency and Fondation de France., Simon, Marie Francoise, Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, Microarrays, lcsh:Medicine, 030204 cardiovascular system & hematology, Cardiovascular, Bioinformatics, Diagnostic Radiology, Ventricular Dysfunction, Left, 0302 clinical medicine, Risk Factors, Natriuretic Peptide, Brain, Pathology, Leukocytes, lcsh:Science, Oligonucleotide Array Sequence Analysis, Principal Component Analysis, 0303 health sciences, education.field_of_study, Multidisciplinary, Medical treatment, Statistics, Models, Cardiovascular, Genomics, Middle Aged, Clinical Laboratory Sciences, Functional Genomics, 3. Good health, Echocardiography, Cardiology, Medicine, Female, DNA microarray, medicine.symptom, Radiology, Research Article, Adult, medicine.medical_specialty, Population, Biostatistics, Asymptomatic, Young Adult, 03 medical and health sciences, Diagnostic Medicine, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, Biology, Aged, 030304 developmental biology, Heart Failure, Receiver operating characteristic, business.industry, Gene Expression Profiling, lcsh:R, Computational Biology, Reproducibility of Results, medicine.disease, Gene expression profiling, Gene Expression Regulation, ROC Curve, Heart failure, lcsh:Q, Genome Expression Analysis, business, Preclinical stage, Mathematics, Biomarkers, Software, General Pathology
Abstract: International audience; BACKGROUND: The preclinical stage of systolic heart failure (HF), known as asymptomatic left ventricular dysfunction (ALVD), is diagnosed only by echocardiography, frequent in the general population and leads to a high risk of developing severe HF. Large scale screening for ALVD is a difficult task and represents a major unmet clinical challenge that requires the determination of ALVD biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: 294 individuals were screened by echocardiography. We identified 9 ALVD cases out of 128 subjects with cardiovascular risk factors. White blood cell gene expression profiling was performed using pangenomic microarrays. Data were analyzed using principal component analysis (PCA) and Significant Analysis of Microarrays (SAM). To build an ALVD classifier model, we used the nearest centroid classification method (NCCM) with the ClaNC software package. Classification performance was determined using the leave-one-out cross-validation method. Blood transcriptome analysis provided a specific molecular signature for ALVD which defined a model based on 7 genes capable of discriminating ALVD cases. Analysis of an ALVD patients validation group demonstrated that these genes are accurate diagnostic predictors for ALVD with 87% accuracy and 100% precision. Furthermore, Receiver Operating Characteristic curves of expression levels confirmed that 6 out of 7 genes discriminate for left ventricular dysfunction classification. CONCLUSIONS/SIGNIFICANCE: These targets could serve to enhance the ability to efficiently detect ALVD by general care practitioners to facilitate preemptive initiation of medical treatment preventing the development of HF.
Published: 2011
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237. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue

Author: Lucie eGeurts, Vladimir eLazarevic, Muriel eDerrien, Amandine eEverard, Marie eVan Roye, Claude eKnauf, Philippe eValet, Myriam eGirard, Giulio G Muccioli, Patrice eFrancois, Willem M de Vos, Jacques eSchrenzel, Nathalie M Delzenne, Patrice D. eCani, Metabolism and nutrition research group, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Louvain Drug Research Institute, Genomic research lab, Geneva University Hospital (HUG), Laboratory of Microbiology, Wageningen University and Research [Wageningen] (WUR), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioanalysis and pharmacology of bioactive lipids laboratory, Bioanalysis and Pharmacology of Bioactive Lipids laboratory (LDRI), Department of Veterinary Biosciences [Helsinki], Faculty of Veterinary Medicine [Helsinki], University of Helsinki-University of Helsinki, Laboratory of bacteriology, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Louvain Drug Research Institute (LDRI), JacquesSchren-zeland Patrice François were supported by grants fromthe Swiss National Science Foundation, #31003A-124717/1and3100A0-116075, respectively. Nathalie M. Delzenne and Patrice D. Cani are recipients of FSR and FRSM grants (Fonds spéciaux de recherches, UCL, Belgium, Fonds de la recherche scientifique médicale, Belgium)., Simon, Marie Francoise, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, and UCL - SSS/LDRI - Louvain Drug Research Institute
Subjects: Microbiology (medical), medicine.medical_specialty, LPS, lcsh:QR1-502, Adipose tissue, 030209 endocrinology & metabolism, Inflammation, Gut microbiota, Gut flora, Microbiology, digestive system, lcsh:Microbiology, 03 medical and health sciences, 0302 clinical medicine, Microbiologie, Internal medicine, medicine, Glucose homeostasis, 030304 developmental biology, Original Research, VLAG, Endocannabinoid, 2. Zero hunger, ddc:616, 0303 health sciences, biology, gut microbiota, Leptin, Type 2 diabetes, type2diabetes, endocannabinoid, biology.organism_classification, metabolic endotoxemia, Endocannabinoid system, Metabolic endotoxemia, Apelin, Endocrinology, apelin, inflammation, APJ, gutmicrobiota, type 2 diabetes, medicine.symptom, Hormone
Abstract: Growing evidence supports the role of gut microbiota in the development of obesity, type 2 diabetes and low-grade inflammation. The endocrine activity of adipose tissue has been found to contribute to the regulation of glucose homeostasis and low-grade inflammation. Among the key hormones produced by this tissue, apelin has been shown to regulate glucose homeostasis. Recently, it has been proposed that gut microbiota participate in adipose tissue metabolism via the endocannabinoid system and gut microbiota-derived compounds, namely lipopolysaccharide (LPS). We have investigated gut microbiota composition in obese and diabetic leptin-resistant mice (db/db) by combining pyrosequencing and phylogenetic microarray analysis of 16S ribosomal RNA gene sequences. We observed a significant higher abundance of Firmicutes, Proteobacteria and Fibrobacteres phyla in db/db mice compared to lean mice. The abundance of 10 genera was significantly affected by the genotype. We identified the roles of the endocannabinoid system and LPS in the regulation of apelinergic system tone (apelin and APJ mRNA expression) in genetic obese and diabetic mice. By using in vivo and in vitro models, we have demonstrated that both the endocannabinoid system and low-grade inflammation differentially regulate apelin and APJ mRNA expression in adipose tissue. Finally, deep-gut microbiota profiling revealed that the gut microbial community of type 2 diabetic mice is significantly different from that of their lean counterparts. This indicates specific relationships between the gut microbiota and the regulation of the apelinergic system. However, the exact roles of specific bacteria in shaping the phenotype of db/db mice remain to be determined.
Published: 2011
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238. CD14 Modulates Inflammation-Driven Insulin Resistance

Author: Antonio Zorzano, Aurélie Waget, José María Moreno-Navarrete, Sofia Pérez del Pulgar, Joan Vendrell, Matteo Serino, José Manuel Fernández-Real, Elodie Luche, Matilde R. Chacón, Wifredo Ricart, Rémy Burcelin, Eleonora Sorianello, Francesc Carmona Pontaque, Alex Sánchez-Pla, Simon, Marie Francoise, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Unit of Endocrinology and Nutrition, University Hospital of Tarragona 'Joan XXIII'-CIBERDEM Tarragona, Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona (UB)-Facultat de Biologia-Institute for Research in Biomedicine-CIBERDEM, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departament d'Estadística, Universitat de Barcelona (UB)-Facultat de Biologia, Unitat d'Estadística i Bioinformatica, and Vall d'Hebron University Hospital [Barcelona]
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, CD14, medicine.medical_treatment, Cellular differentiation, Lipopolysaccharide Receptors, Adipose tissue, Mice, Obese, 030209 endocrinology & metabolism, Inflammation, Biology, Pathophysiology, 03 medical and health sciences, Mice, 0302 clinical medicine, Insulin resistance, Internal medicine, Internal Medicine, medicine, Adipocytes, Animals, Humans, 030304 developmental biology, Bone Marrow Transplantation, Mice, Knockout, 0303 health sciences, Tumor Necrosis Factor-alpha, Insulin, Gene Expression Profiling, Bone Marrow Stem Cell, Cell Differentiation, medicine.disease, Dietary Fats, Endocrinology, Adipose Tissue, Tumor necrosis factor alpha, medicine.symptom, Insulin Resistance
Abstract: OBJECTIVE The study objective was to evaluate the possible role of the macrophage molecule CD14 in insulin resistance. RESEARCH DESIGN AND METHODS The effects of recombinant human soluble CD14 (rh-sCD14) on insulin sensitivity (clamp procedure) and adipose tissue gene expression were evaluated in wild-type (WT) mice, high fat–fed mice, ob/ob mice, and CD14 knockout (KO) mice. We also studied WT mice grafted with bone marrow stem cells from WT donor mice and CD14 KO mice. Finally, CD14 was evaluated in human adipose tissue and during differentiation of human preadipocytes. RESULTS rh-sCD14 led to increased insulin action in WT mice, high-fat–fed mice, and ob/ob mice, but not in CD14 KO mice, in parallel to a marked change in the expression of 3,479 genes in adipose tissue. The changes in gene families related to lipid metabolism were most remarkable. WT mice grafted with bone marrow stem cells from WT donor mice became insulin resistant after a high-fat diet. Conversely, WT mice grafted with cells from CD14 KO mice resisted the occurrence of insulin resistance in parallel to decreased mesenteric adipose tissue inflammatory gene expression. Glucose intolerance did not worsen in CD14 KO mice grafted with bone marrow stem cells from high fat–fed WT mice when compared with recipient KO mice grafted with cells from CD14 KO donor mice. CD14 gene expression was increased in whole adipose tissue and adipocytes from obese humans and further increased after tumor necrosis factor-α. CONCLUSIONS CD14 modulates adipose tissue inflammatory activity and insulin resistance.
Published: 2011
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239. [Tubulo-interstitial fibrosis: an emerging major health problem]

Author: Julie, Klein, Mathieu, Miravete, Bénédicte, Buffin-Meyer, Joost P, Schanstra, Jean-Loup, Bascands, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Kallikrein-Kinin System, MESH: Cell Hypoxia, Angiotensin-Converting Enzyme Inhibitors, MESH: Extracellular Matrix, Kidney, urologic and male genital diseases, Models, Biological, MESH: Lysophospholipids, Myoblasts, Renin-Angiotensin System, Angiotensin Receptor Antagonists, Mice, MESH: Proteinuria, MESH: Renin-Angiotensin System, Animals, Humans, MESH: Animals, MESH: Incidence, MESH: Myoblasts, MESH: Intercellular Signaling Peptides and Proteins, MESH: Mice, MESH: Cytokines, MESH: Humans, Incidence, Macrophages, MESH: Angiotensin-Converting Enzyme Inhibitors, MESH: Models, Biological, MESH: Macrophages, MESH: Kallikrein-Kinin System, MESH: Kidney, Fibroblasts, MESH: Chemokines, Cell Hypoxia, Extracellular Matrix, Proteinuria, MESH: Angiotensin Receptor Antagonists, MESH: Morbidity, MESH: Kidney Failure, Chronic, MESH: Fibroblasts, Disease Progression, Cytokines, Intercellular Signaling Peptides and Proteins, Kidney Failure, Chronic, Nephritis, Interstitial, MESH: Disease Progression, Chemokines, Lysophospholipids, Morbidity, MESH: Nephritis, Interstitial
Abstract: International audience; The incidence of chronic kidney disease leading to end-stage renal disease has significantly increased and may reach epidemic proportions over the next decade. Regardless of the initial insult, the progression of most forms of renal disease results in tubulo-interstitial fibrosis. This has been closely correlated to the future appearance of renal failure and has therefore been associated with poor long-term prognosis. New molecules and agents to limit the development of tubulo-interstitial fibrosis and slow down the progression towards end-stage renal disease are needed. In the past twenty years, many efforts have been made to understand the mechanisms of tubulo-intersititial fibrosis with the final goal to develop new therapeutic strategies. In this context, this review will focus on the mechanisms and factors involved in the development and the progression of renal fibrosis and will discuss the new promising therapeutic strategies in animal and humans.
Published: 2011
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240. G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors

Author: Gilles Mourier, Nicolas Gilles, Jean-Michel Senard, Loïc Quinton, Céline Galés, Denis Servent, Colette Denis, Céline Rouget, Arhamatoulaye Maïga, Stefano Palea, Philippe Lluel, Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de spectrométrie de masse, Université de Liège-Groupe Interdisciplinaire de Génoprotéomique Appliquée-Département de Chimie, UROsphere S.A.S., Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Faculte des Sciences Pharmaceutiques, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Urosphère SAS, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), ANR-06-PCVI-0008,gpcrcanotox,Etudes structurales et fonctionnelles des récepteurs couplés aux protéines G et des canaux ioniques à l'aide de toxines peptidiques.(2006), and ANR-07-EMPB-0001,adrenergicpeptide,Preuve de concept in vivo de l'action antagoniste sélective de l'AdTx1 sur le sous-type alpha1a du récepteur adrénergique en vue de son utilisation contre l'hypertrophie bénigne de la prostate.(2007)
Subjects: Male, medicine.medical_specialty, Adrenergic Antagonists, Adrenergic receptor, G protein, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Venom, Biology, Pharmacology, Toxicology, Ligands, Receptors, G-Protein-Coupled, 03 medical and health sciences, 0302 clinical medicine, In vivo, Internal medicine, Muscarinic acetylcholine receptor, Drug Discovery, medicine, Animals, Amino Acid Sequence, Elapidae, Postoperative Period, Rats, Wistar, Receptor, 030304 developmental biology, G protein-coupled receptor, Elapid Venoms, 0303 health sciences, 3. Good health, Rats, Receptors, Adrenergic, Endocrinology, Drug development, Hypotension, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: International audience; At a time when pharmaceutical companies are having trouble finding new low MW drugs and when biologics are becoming more common, animal venoms could constitute an underexploited source of novel drug candidates. We looked for identifying novel animal toxins active against G protein-coupled receptors (GPCR), the most frequently exploited class of treatment targets, with the aim to develop novel research tools and drug candidates. Screening of green mamba ($Dendroaspis\ angusticeps$) venom against adrenoceptors identified two novel venom peptides. $\rho$-Da1a shown an affinity of 0.35 nM for the $\alpha$1a-AR while $\rho$-Da1b displayed affinities between 14 and 73 nM for the three $\alpha$2-ARs. These two venom peptides have sequences similar to those of muscarinic toxins and belong to the three-finger-fold protein family. $\alpha$1a-AR is the primary target for the treatment of prostate hypertrophy. In vitro and in vivo tests demonstrated that ρ-Da1a reduced prostatic muscle tone as efficiently as tamsulosin (an antagonist presently used), but with fewer cardiovascular side effects. $\alpha$2-ARs are the prototype of GPCRs not currently used as treatment targets due to a lack of specific ligands. Blockage of these receptors increases intestinal motility, which may be compromised by abdominal surgery and reduces orthosteric hypotension. In vitro and in vivo tests demonstrated that ρ-Da1b antagonizes $\alpha$2-ARs in smooth muscles and increased heart rate and blood catecholamine concentrations. These results highlight possible exploitation of $\rho$-Da1a and $\rho$-Da1b in important pathologies.
Published: 2010
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241. Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications

Author: Anne-Coline Laurent, Magali Breckler, Bertrand Crozatier, Frank Lezoualc'h, Eric Morel, Magali Berthouze, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Université Paris-Sud - Paris 11 (UP11), Signalisation et physiopathologie cardiaque, Université Paris-Sud - Paris 11 (UP11)-IFR141-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Scaffold protein, 0303 health sciences, Small G Protein, Cell Biology, Biology, Cell biology, Receptors, G-Protein-Coupled, 03 medical and health sciences, 0302 clinical medicine, rap GTP-Binding Proteins, Second messenger system, Cyclic AMP, Guanine Nucleotide Exchange Factors, Rap1, Guanine nucleotide exchange factor, Signal transduction, Protein kinase A, 030217 neurology & neurosurgery, 030304 developmental biology, G protein-coupled receptor, Signal Transduction
Abstract: International audience; Epac proteins respond to the second messenger cyclic AMP (cAMP) and are activated by Gs coupled receptors. They act as specific guanine nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2 of the Ras family. A plethora of studies using 8-pCPT-2'-O-Me-cAMP, an Epac agonist, has revealed the importance of these multi-domain proteins in the control of key cellular functions such as cell division, migration, growth and secretion. Epac and protein kinase A (PKA) may act independently but are often associated with the same biological process, in which they fulfill either synergistic or opposite effects. In addition, compelling evidence is now accumulating about the formation of molecular complexes in distinct cellular compartments that influence Epac signaling and cellular function. Epac is spatially and temporally regulated by scaffold protein and its effectors are interconnected with other signaling pathways. Pathophysiological changes in Epac signaling may underlie certain diseases.
Published: 2010
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242. Endothelial estrogen receptor {alpha} plays an essential role in the coronary and myocardial protective effects of estradiol in ischemia/reperfusion

Author: Françoise Lenfant, Ji Gao, Isabelle Remy-Jouet, Isabelle Fourquaux, Jean-Paul Henry, Christian Thuillez, Julie Favre, Audrey Billon-Galés, Vincent Richard, Jean-François Arnal, Pharmacologie des Dysfonctionnements Endotheliaux et Myocardiques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Microscopie Électronique Appliquée à la Biologie (CMEAB), Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Simon, Marie Francoise, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Rangueil, and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul)
Subjects: Time Factors, Vasodilator Agents, Estrogen receptor, Blood Pressure, Vasodilation, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, MESH: Drug Implants, MESH: Dose-Response Relationship, Drug, Mice, 0302 clinical medicine, Heart Rate, MESH: Coronary Vessels, MESH: Animals, MESH: Endothelial Cells, Endothelial dysfunction, MESH: Heart Rate, MESH: Bone Marrow Transplantation, MESH: Estrogen Receptor alpha, Bone Marrow Transplantation, Drug Implants, Mice, Knockout, 0303 health sciences, Estradiol, Estrogen Replacement Therapy, MESH: Reactive Oxygen Species, MESH: Blood Pressure, Coronary Vessels, MESH: Myocardial Reperfusion Injury, medicine.anatomical_structure, MESH: Uterus, Female, MESH: Estradiol, Cardiology and Cardiovascular Medicine, MESH: Transplantation Chimera, medicine.medical_specialty, MESH: Myocardium, Endothelium, medicine.drug_class, Ovariectomy, Ischemia, MESH: Ovariectomy, Myocardial Reperfusion Injury, MESH: Vasodilation, 03 medical and health sciences, In vivo, MESH: Mice, Inbred C57BL, Internal medicine, medicine, Animals, MESH: Mice, 030304 developmental biology, Transplantation Chimera, Dose-Response Relationship, Drug, business.industry, Myocardium, Uterus, MESH: Time Factors, Estrogen Receptor alpha, Endothelial Cells, medicine.disease, MESH: Estrogen Replacement Therapy, MESH: Vasodilator Agents, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Estrogen, MESH: Disease Models, Animal, Reactive Oxygen Species, business, MESH: Female, Ex vivo
Abstract: Objective— To assess the coronary endothelial protective effects of 17β-estradiol (E2) and the role of estrogen receptor (ER) α in ischemia/reperfusion (I/R). Methods and Results— E2 exerts protective effects in cardiac I/R. However, the implication in vivo of the endothelium and the cellular targets of the anti-ischemic effects of E2 are unknown. Mice were subjected to I/R (30 minutes of I and 1 hour of R) in vivo, after which acetylcholine-induced relaxation of isolated coronary segments was assessed ex vivo. I/R induced a coronary endothelial dysfunction in untreated ovariectomized mice that was prevented by long-term treatment with E2 in wild-type, but not in ERα −/− , mice. Chimeric mice inactivated for ERα in the hematopoietic compartment remained protected by E2. Further inactivation of endothelial ERα abolished the protective action of E2 on coronary endothelial function in Tie2-Cre(+) ERα f/f mice. More importantly, E2 significantly limited infarct size in wild-type mice but not in mice deficient in endothelial ERα, even in the presence of hematopoietic ERα. Conclusion— Endothelial ERα plays a crucial role in the E2-induced prevention of endothelial dysfunction after I/R. To our knowledge, we demonstrate for the first time, by using unique genetically modified mice, that targeting endothelial protection per se can confer cardiomyocyte protection in I/R.
Published: 2010
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243. Adipose-derived stromal cells: cytokine expression and immune cell contaminants

Author: Coralie Sengenès, Jean Galitzky, Pauline Decaunes, Anne Bouloumié, David Estève, Alexia Zakaroff-Girard, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), and Université Paul Sabatier - Toulouse 3 ( UPS ) -Hôpital de Rangueil-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: MESH : Cytokines, MESH : Lymphocytes, Cell, Lipopolysaccharide Receptors, Adipose tissue, MESH : Adipocytes, MESH: Flow Cytometry, Antigens, CD34, Cell Separation, 030204 cardiovascular system & hematology, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : RNA, Adipocytes, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Endothelial Cells, Lymphocytes, 0303 health sciences, MESH: Cytokines, biology, Chemistry, MESH: Antigens, CD14, Reverse Transcriptase Polymerase Chain Reaction, MESH : Reverse Transcriptase Polymerase Chain Reaction, Cell Differentiation, Flow Cytometry, 3. Good health, Cell biology, Platelet Endothelial Cell Adhesion Molecule-1, medicine.anatomical_structure, Adipose Tissue, MESH : Antigens, CD31, MESH : Antigens, CD34, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Antibody, MESH : Cell Differentiation, MESH: Adipose Tissue, MESH: Cell Differentiation, Stromal cell, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Flow Cytometry, MESH : Adipose Tissue, MESH: Cell Separation, 03 medical and health sciences, Immune system, MESH: RNA, Lymph node stromal cell, medicine, Humans, Progenitor cell, MESH: Adipocytes, 030304 developmental biology, MESH: Humans, MESH : Endothelial Cells, MESH : Humans, Cytokine expression, Endothelial Cells, MESH: Antigens, CD31, MESH: Antigens, CD34, MESH : Antigens, CD14, MESH : Stromal Cells, MESH : Cell Separation, Immunology, biology.protein, RNA, MESH: Lymphocytes, MESH: Stromal Cells, Stromal Cells
Abstract: International audience; The present method describes an immunoselection/depletion approach to isolate the native human adipose tissue-derived progenitor cells that are free from endothelial cells and immune cells by the use of magnetic nanobeads and microbeads coupled to antibodies. Moreover, methods to isolate and to analyse the distinct cell populations that constitute the microenvironment of the human adipose tissue progenitor cells, i.e. mature adipocytes, endothelial cells, and macrophages, are mentioned.
Published: 2010
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244. Strong cytotoxic effect of the bradykinin antagonist BKM-570 in ovarian cancer cells--analysis of the molecular mechanisms of its antiproliferative action

Author: Stephanie, Jutras, Magdalena, Bachvarova, Mamadou, Keita, Jean-Loup, Bascands, Anne-Marie, Mes-Masson, John M, Stewart, Lajos, Gera, Dimcho, Bachvarov, Simon, Marie Francoise, Department of Molecular Medicine [Québec], Université Laval [Québec] (ULaval), Cancer Research Centre (CHUQ), Centre Hospitalier Universitaire de Québec-Hôpital L'Hotel-Dieu de Québec, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine, Université de Montréal (UdeM), Centre Hospitalier de l'Université de Montréal (CHUM), Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz [Aurora], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Ovarian Neoplasms, endocrine system diseases, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Receptors, Bradykinin, Antineoplastic Agents, Drug Synergism, Bradykinin, Cell Line, Tumor, Humans, Tyrosine, Female, Cisplatin, Drug Screening Assays, Antitumor, Cell Proliferation, Oligonucleotide Array Sequence Analysis
Abstract: International audience; The standard chemotherapy for epithelial ovarian cancer (EOC) patients is currently a combination of taxane and platinum. However, most EOC patients still suffer relapses, and there is an immediate need for the development of novel and more effective therapeutic modalities against this deadly disease. Recently, the nonpeptide bradykinin (BK) antagonist 2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-l-tyrosine-N-(4-amino-2,2,6,6-tetramethyl-piperidyl) amide (BKM-570) was shown to cause impressive growth inhibition of lung and prostate tumors, displaying superior in vivo inhibitory effects than convential chemotherapeutic drugs. Here, we investigated BKM-570 cytotoxic effects in two EOC cell lines, derived from different EOC histopathologies: a clear cell carcinoma (TOV-21), and an endometrioid carcinoma (TOV-112). We showed that BKM-570 effectively inhibited the growth of ovarian cancer cells, as its cytotoxic effects were comparable to those of cisplatin, and were independent of the functional status of BK receptors. Moreover, BKM-570 synergized with cisplatin in inhibiting EOC cell growth. To better understand the molecular mechanisms of the antiproliferative action of this BK antagonist in EOC cells, we performed gene expression profiling in TOV-21 and TOV-112 cells following treatment with 10 μM BKM-570 for 24 h. BKM-570 displayed similar cytotoxic effects in the two cell lines analyzed, as genes with previously shown involvement in apoptosis/antiapoptosis and cell adhesion were proportionally upregulated and downregulated in both cell lines, whereas genes involved in basic cellular mechanisms, including cell growth and maintenance, metabolism, cell cycle control, inflammatory and immune response, signal transduction, protein biosynthesis, transcription regulation, and transport, were predominantly downregulated upon treatment. Our data are indicative of the therapeutic potential of BKM-570 and related compounds in EOC management.
Published: 2010
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245. Worsening of obesity and metabolic status yields similar molecular adaptations in human subcutaneous and visceral adipose tissue: decreased metabolism and increased immune response

Author: Nathalie Viguerie, Vladimir Stich, Petra Šrámková, Michaela Siklova-Vitkova, Anne Bouloumié, Dominique Langin, Zuzana Kovacova, Eva Klimcakova, Adriana Márquez-Quiñones, Balbine Roussel, Jindra Hejnova, Michaela Kovacikova, Marion Combes, Franco-czech Laboratory for clinical research on obesity, Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherche 150, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, OB Clinic, AVENIR team 'Vascular network, progenitor cells and immune cells', Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Laboratoire de Biochimie, CHU Toulouse [Toulouse]-Institut de Biologie de Purpan, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise
Subjects: Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Adipose tissue, Gene Expression, Overweight, Biochemistry, MESH: Glucose Clamp Technique, MESH: Down-Regulation, 0302 clinical medicine, Endocrinology, MESH: Metabolic Syndrome X, MESH: Obesity, MESH: Aged, Metabolic Syndrome, 0303 health sciences, MESH: Middle Aged, Glucose clamp technique, Middle Aged, MESH: Insulin Resistance, Female, medicine.symptom, Adult, medicine.medical_specialty, MESH: Gene Expression, Subcutaneous Fat, Down-Regulation, 030209 endocrinology & metabolism, Context (language use), Biology, Intra-Abdominal Fat, 03 medical and health sciences, Insulin resistance, MESH: Subcutaneous Fat, Internal medicine, medicine, Humans, Obesity, MESH: Intra-Abdominal Fat, 030304 developmental biology, Aged, MESH: Humans, Biochemistry (medical), nutritional and metabolic diseases, MESH: Adult, medicine.disease, Gene expression profiling, Glucose Clamp Technique, Metabolic syndrome, Insulin Resistance, MESH: Female
Abstract: Context: It is not known whether biological differences reported between sc adipose tissue (SAT) and visceral adipose tissue (VAT) depots underlie the pathogenicity of visceral fat. Objective: We compared SAT and VAT gene expression according to obesity, visceral fat accumulation, insulin resistance, and presence of the metabolic syndrome. Design: Subjects were assigned into four groups (lean, overweight, obese, and obese with metabolic syndrome). Setting: Subjects were recruited at a university hospital. Patients: Thirty-two women were included. Main Outcome Measures: Anthropometric measurements, euglycemic-hyperinsulinemic clamps, blood analyses, and computed tomography scans were performed, and paired samples of SAT and VAT were obtained for DNA microarray-based gene expression profiling. Results: Considering the two fat depots together, 1125 genes were more and 1025 genes were less expressed in lean compared with metabolic syndrome subjects. Functional annotation clustering showed, from lean to metabolic syndrome subjects, progressive down-regulation of metabolic pathways including branched-chain amino acid, fatty acid, carbohydrate, and mitochondrial energy metabolism and up-regulation of immune response genes involved in toll-like receptor, TNF, nuclear factor-κB, and apoptosis pathways. Metabolism and immune response genes showed an opposite correlation with fat mass, fat distribution, or insulin resistance indices. These associations were similar in SAT and VAT, although about 1000 genes showed differential expression between SAT and VAT. Conclusions: The increase in adiposity and the worsening of metabolic status are associated with a coordinated down-regulation of metabolism-related and up-regulation of immune response-related gene expression. Molecular adaptations in SAT prove as discriminating as those in VAT.
Published: 2010
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246. Synthesis of cytotoxic aza analogues of jaspine B

Author: Thierry Levade, Nathalie Andrieu-Abadie, Arnaud Rives, Sonia Ladeira, Yves Génisson, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative Toulousaine en Chimie Moléculaire (SFTCM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Pyrrolidines, 010405 organic chemistry, Stereochemistry, Organic Chemistry, Melanoma, Experimental, Tumor cells, Stereoisomerism, Metabolism, 010402 general chemistry, 01 natural sciences, Sphingolipid, Chemical synthesis, Pyrrolidine, 0104 chemical sciences, chemistry.chemical_compound, Mice, chemistry, Sphingosine, Cell Line, Tumor, Cytotoxic T cell, Animals, Humans, Staudinger reaction, Cytotoxicity
Abstract: International audience; A straightforward access to pyrrolidine-based analogues of jaspine B was developed. Five stereoisomers were prepared including the all-cis derivatives presenting the configuration of the natural anhydrophytosphingosine. The synthesis of the latter relied on an original Staudinger-type cyclization process. The compounds were evaluated regarding their ability to alter tumor cells' viability and to interfere with the metabolism of sphingolipids.
Published: 2010
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247. Caspase-10-Dependent Cell Death in Fas/CD95 Signalling Is Not Abrogated by Caspase Inhibitor zVAD-fmk

Author: Thierry Levade, Nicole Therville, Nathalie Andrieu-Abadie, Delphine Milhas, Bruno Ségui, Hervé Benoist, Elodie Lafont, Justin Teissié, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Programmed cell death, Blotting, Western, lcsh:Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cysteine Proteinase Inhibitors, Jurkat cells, Fas ligand, Cell Biology/Cell Signaling, Amino Acid Chloromethyl Ketones, 03 medical and health sciences, Jurkat Cells, 0302 clinical medicine, Humans, fas Receptor, lcsh:Science, Caspase 10, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Cell Death, lcsh:R, Transfection, Cell Biology/Cellular Death and Stress Responses, Hematology/Acute Lymphoblastic Leukemia, Fas receptor, Flow Cytometry, Caspase Inhibitors, Cell biology, Apoptosis, 030220 oncology & carcinogenesis, lcsh:Q, Signal transduction, biological phenomena, cell phenomena, and immunity, Research Article, HeLa Cells, Signal Transduction
Abstract: BACKGROUND: Upon CD95/Fas ligation, the initiator caspase-8 is known to activate effector caspases leading to apoptosis. In the presence of zVAD-fmk, a broad-spectrum caspase inhibitor, Fas engagement can also trigger an alternative, non-apoptotic caspase-independent form of cell death, which is initiated by RIP1. Controversy exists as to the ability of caspase-10 to mediate cell death in response to FasL (CD95L or CD178). Herein, the role of caspase-10 in FasL-induced cell death has been re-evaluated. METHODOLOGY AND PRINCIPAL FINDINGS: The present study shows that FasL-induced cell death was completely impaired in caspase-8- and caspase-10-doubly deficient (I9-2e) Jurkat leukaemia T-cell lines. Over-expressing of either caspase-8 or caspase-10 in I9-2e cells triggered cell death and restored sensitivity to FasL, further arguing for a role of both initiator caspases in Fas apoptotic signalling. In the presence of zVAD-fmk, FasL triggered an alternative form of cell death similarly in wild-type (A3) and in caspase-8-deficient Jurkat cells expressing endogenous caspase-10 (clone I9-2d). Cell death initiated by Fas stimulation in the presence of zVAD-fmk was abrogated in I9-2e cells as well as in HeLa cells, which did not express endogenous caspase-10, indicating that caspase-10 somewhat participates in this alternative form of cell death. Noteworthy, ectopic expression of caspase-10 in I9-2e and HeLa cells restored the ability of FasL to trigger cell death in the presence of zVAD-fmk. As a matter of fact, FasL-triggered caspase-10 processing still occurred in the presence of zVAD-fmk. CONCLUSIONS AND SIGNIFICANCE: Altogether, these data provide genetic evidence for the involvement of initiator caspase-10 in FasL-induced cell death and indicate that zVAD-fmk does not abrogate caspase-10 processing and cytotoxicity in Fas signalling. Our study also questions the existence of an alternative caspase-independent cell death pathway in Fas signalling.
Published: 2010
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248. Physiologic and pathologic changes of platelets in pregnancy

Author: Olivier Parant, Christophe Vayssière, Bernard Payrastre, Marie-Cécile Valéra, Jean-François Arnal, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Gynécologie [CHU Toulouse], Pôle Femme-Mère-Couple [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de gynécologie obstétrique, CHU Toulouse [Toulouse]-Hôpital Paule de Viguier, CHU Toulouse [Toulouse], Laboratoire d'Hématologie [Purpan], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]
Subjects: Blood Platelets, medicine.medical_specialty, MESH: Pre-Eclampsia, MESH: Bernard-Soulier Syndrome, MESH: Pregnancy Complications, Hematologic, 030204 cardiovascular system & hematology, MESH: Hypertension, Preeclampsia, Miscarriage, 03 medical and health sciences, 0302 clinical medicine, MESH: Pregnancy, Pre-Eclampsia, Pregnancy, medicine, Humans, Platelet, MESH: Platelet Count, Thrombus, reproductive and urinary physiology, MESH: Thrombocytopenia, MESH: Blood Platelets, 030219 obstetrics & reproductive medicine, MESH: Humans, Obstetrics, business.industry, Platelet Count, Incidence (epidemiology), Pregnancy Complications, Hematologic, Bernard-Soulier Syndrome, Hematology, General Medicine, medicine.disease, Thrombosis, Thrombocytopenia, 3. Good health, First trimester, MESH: Blood Platelet Disorders, Hypertension, Female, Blood Platelet Disorders, business, MESH: Female
Abstract: International audience; Platelets are key players in haemostasis and thrombus formation. Defects affecting platelets during pregnancy can lead to heterogeneous complications, such as thrombosis, first trimester miscarriage and postpartum haemorrhage. The incidence of complications is increased in women who have heritable platelet function disorders. Modifications of platelet count or platelet functions during normal pregnancy and preeclampsia will be summarized and the management of pregnant women with heritable platelet function disorders will be discussed.
Published: 2010
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249. Skeletal muscle lipase content and activity in obesity and type 2 diabetes

Author: Aline Mairal, Luc J. C. van Loon, Ellen E. Blaak, Dominique Hansen, Matthijs K. C. Hesselink, Gijs H. Goossens, Cedric Moro, Dominique Langin, Johan W. E. Jocken, Department of Human Biology, Maastricht University [Maastricht], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Jessa Hospital and Rehabilitation and Healthcare Research Center, Provinciale Hogeschool Limburg University College, Department of Human Movement Sciences, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Humane Biologie, Nutrition and Movement Sciences, RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, and RS: NUTRIM - R1 - Metabolic Syndrome
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Arbitrary unit, Lipolysis, Clinical Biochemistry, Triacylglycerol lipase, Context (language use), Biochemistry, MESH: Lipase, Endocrinology, Insulin resistance, Thinness, Reference Values, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, MESH: Obesity, Humans, MESH: Lipolysis, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, Lipase, Muscle, Skeletal, MESH: Muscle, Skeletal, MESH: Sterol Esterase, MESH: Thinness, MESH: Humans, biology, Biochemistry (medical), MESH: Reference Values, Skeletal muscle, Sterol Esterase, medicine.disease, MESH: Case-Control Studies, MESH: Male, MESH: Insulin Resistance, Lipoprotein Lipase, medicine.anatomical_structure, Diabetes Mellitus, Type 2, Case-Control Studies, Adipose triglyceride lipase, biology.protein, Insulin Resistance, MESH: Diabetes Mellitus, Type 2, MESH: Lipoprotein Lipase
Abstract: Context: The obese insulin-resistant state is characterized by elevated lipid storage in skeletal muscle tissue. Objective: We tested whether differences in muscle triacylglycerol (TAG) and diacylglycerol (DAG) lipase content and activity are associated with incomplete in vivo lipolysis and lipid accumulation. Design and Patients: Two case-control studies were conducted on skeletal muscle biopsies from lean (n = 13) and obese (n = 10) men (study 1) and from 11 nonobese type 2 diabetic (T2D), obese T2D, and healthy normoglycemic men (study 2). Main Outcome Measures: Skeletal muscle lipase protein content and activity and muscle lipid content (TAG and DAG) were determined. Results: Skeletal muscle hormone-sensitive lipase protein content was lower (0.39 +/- 0.07 vs. 1.00 +/- 0.19 arbitrary units; P = 0.004) and adipose triglyceride lipase protein content was higher in obese men compared with lean controls (2.17 +/- 0.40 vs. 0.42 +/- 0.23 arbitrary units; P = 0.008). This apparent difference in lipase content was accompanied by a 60% lower ratio of DAG to TAG hydrolase activity in the obese men (11.4 +/- 2.3 vs. 26.5 +/- 7.3 nmol/h . mg; P = 0.045), implying incomplete lipolysis. Lower hormone-sensitive lipase and higher adipose triglyceride lipase content was confined to obesity per se, because it was observed solely in obese T2D men but not in healthy normoglycemic controls and nonobese T2D men. Muscle total DAG content was not higher in obese men but was even lower (6.2 +/- 0.7 vs. 9.4 +/- 0.9 mumol/mg dry weight; P = 0.017). TAG content did not differ between groups (84.7 +/- 18.9 vs. 70.4 +/- 12.4 mumol/mg dry weight; P = 0.543). Conclusions: Our data do not support an important role of total muscle DAG content in the development of insulin resistance in obese men.
Published: 2010
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250. Pathological aspects of lipid peroxidation

Author: Giuseppe Poli, José C. E. Serrano, Giovanni E. Mann, Reinald Pamplona, János Fehér, Nathalie Augé, Victoria Ayala, Gabriella Lengyel, Werner Siems, Rainer Brenke, Shlomo Sasson, Kamelija Zarkovic, Robert Salvayre, Guy Cohen, Jordi Boada, Tilman Grune, Anne Nègre-Salvayre, Sarah J. Chapple, Richard C.M. Siow, Manuel Portero-Otin, Ingrid Wiswedel, Yael Riahi, Neven Zarkovic, Ofer Shamni, Huveyda Basaga, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Metabolic Pathophysiology Research GroupDepartment of Basic Medical Sciences, Universitat de Lleida, Biological Sciences and Bioengineering Program, Sabanci University [Istanbul], Departament de Medicina Experimental, Hufeland Hospital, Cardiovascular Division, King‘s College London, The Hebrew University of Jerusalem (HUJ), 2nd Department of Medicine, Semmelweis University [Budapest], Institute of Biological Chemistry and Nutrition, University of Hohenheim, Department of Clinical and Biological Sciences, San Luigi Hospital-University of Turin, Department of Pharmacology, The Hebrew University of Jerusalem (HUJ)-Institute for Drug Research, Cités, Territoires, Environnement et Sociétés (CITERES), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Research Institute of Physiotherapy and Gerontology, Institute of Medical Education Bad Harzburg-KortexMed Institute of Medical Education Bad Harzburg, Department of Pathological Biochemistry, Medical Faculty of the Otto-von-Guericke-University, Department of Neuropathology, University of Zagreb-Clinical Hospital Center Zagreb, Rudjer Boskovic Institute, Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT), Rudjer Boskovic Institute [Zagreb], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Tours, Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Università degli studi di Torino = University of Turin (UNITO)-San Luigi Hospital
Subjects: Aging, [SDV]Life Sciences [q-bio], Bioinformatics, medicine.disease_cause, Biochemistry, MESH: Lipid Peroxidation, MESH: Atherosclerosis, MESH: Neurodegenerative Diseases, Lipid peroxidation, chemistry.chemical_compound, Liver disease, 0302 clinical medicine, Neoplasms, MESH: Aging, MESH: Animals, MESH: Neoplasms, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, MESH: Oxidative Stress, Liver Diseases, Fatty liver, Neurodegenerative Diseases, General Medicine, 3. Good health, lipid peroxidation, 4-hydroxynonenal, medicine.medical_specialty, MESH: Diabetes Mellitus, MESH: Liver Diseases, oxidative stress, oxidative homeostasis, ROS, 4-Hydroxynonenal, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, liver disease, atherosclerosis, redox equilibrium, cell signalling, oxidized phospholipids, oxysterol, diabetes, 4-hydroxydodecadienal, pre-eclampsia, HELLP syndrome, IUGR, glutathione, redox signaling, Nrf2, antioxidant enzymes, foetal endothelium, renal diseases, lymphoedema, hyperglycaemia, advanced glycation end-products, cancer, Oxysterol, Biology, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Diabetes Mellitus, medicine, Animals, Humans, 030304 developmental biology, MESH: Humans, Atherosclerosis, medicine.disease, Oxidative Stress, Endocrinology, chemistry, Ageing, Lipid Peroxidation, 030217 neurology & neurosurgery, Oxidative stress, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed.
Published: 2010
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